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Pathophysiology, diagnosis, and management of endometriosis

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• Peer review
• Andrew W Horne , professor of gynaecology and reproductive sciences 1 ,
• Stacey A Missmer , professor of obstetrics, gynaecology, and reproductive biology , adjunct professor of epidemiology 2 3
• 1 EXPPECT Edinburgh and MRC Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK
• 2 Michigan State University, Grand Rapids, MI, USA
• 3 Harvard T.H. Chan School of Public Health, Boston, MA, USA
• Correspondence to: A W Horne andrew.horne{at}ed.ac.uk

Endometriosis affects approximately 190 million women and people assigned female at birth worldwide. It is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which in many patients is associated with debilitating painful symptoms. Patients with endometriosis are also at greater risk of infertility, emergence of fatigue, multisite pain, and other comorbidities. Thus, endometriosis is best understood as a condition with variable presentation and effects at multiple life stages. A long diagnostic delay after symptom onset is common, and persistence and recurrence of symptoms despite treatment is common. This review discusses the potential genetic, hormonal, and immunologic factors that lead to endometriosis, with a focus on current diagnostic and management strategies for gynecologists, general practitioners, and clinicians specializing in conditions for which patients with endometriosis are at higher risk. It examines evidence supporting the different surgical, pharmacologic, and non-pharmacologic approaches to treating patients with endometriosis and presents an easy to adopt step-by-step management strategy. As endometriosis is a multisystem disease, patients with the condition should ideally be offered a personalized, multimodal, interdisciplinary treatment approach. A priority for future discovery is determining clinically informative sub-classifications of endometriosis that predict prognosis and enhance treatment prioritization.

Introduction

Endometriosis is a chronic, inflammatory, gynecologic disease marked by the presence of endometrial-like tissue outside the uterus, which affects approximately 10% of women during their reproductive years—190 million women worldwide. 1 In many patients, it is associated with chronic painful symptoms and other comorbidities, including infertility. 2 The health burden of endometriosis includes chronic pain and significant lifetime costs of $27 855 per year per patient, 3 accumulating to annual healthcare costs for endometriosis of approximately $22bn in the US alone and £12.5bn in the UK in treatment, work loss, and healthcare costs. 4 Although more than 50% of adults diagnosed as having endometriosis report onset of severe pelvic pain during adolescence, 5 most young women with endometriosis do not receive timely treatment. Almost 60% of women will see three or more clinicians before a diagnosis of endometriosis is made after an average of seven years with symptoms. 6 Women with endometriosis lose on average 11 hours of work per week, similar to other chronic conditions including type 2 diabetes, Crohn’s disease, and rheumatoid arthritis. 7 Adolescents are at risk of having inadequately remediated symptoms during prime years for social development and life planning, 8 and women must be resilient against inadequately remediated symptoms and emerging comorbidities. Women, healthcare providers, and scientists would benefit from conceptualizing endometriosis as a condition that can affect the whole woman. This includes a better understanding of the risk of subsequent development of autoimmune disease, cancer, and cardiovascular disease and a whole health approach to monitoring and wellbeing. 9

This review is aimed at general practitioners and pediatric specialists who are most likely to interact with patients as signs and symptoms of endometriosis first emerge and from whom early attention and empiric treatment may dramatically shorten the burden; gynecology specialists for whom myths must be dispelled and who must be aware of state of the art knowledge about patient centered treatments; endometriosis specialists who care for women’s endometriosis associated symptoms across the life course; and clinical researchers and scientists who must be inspired to bring their expertise and creativity to answer the fundamental enigmas of endometriosis etiology, informative sub-phenotyping, and novel patient centered treatment.

In this review, we use the terms “woman” and “women.” However, it is important to note that endometriosis can affect all people assigned female at birth.

Sources and selection criteria

We searched PubMed for studies using the term “endometriosis.” We considered all peer reviewed studies published in the English language between 1 January 2010 and 28 February 2022. We also identified references from international guidelines on endometriosis published during this time period. We selected relevant publications outside this timeline on the basis of review of the bibliography. We predefined the priority of study selection for this review according to the level of the evidence (meta-analyses, systematic or scoping reviews, randomized controlled trials (RCTs), prospective cohort studies, case-control studies, cross sectional studies; a priori exclusion of case series and case reports), by sample size (we prioritized studies with larger sample size as well as studies providing precision statistics), by population sampling (we prioritized studies with more diverse populations or with declared sub-population design over narrow population samples), and publication date (we prioritized more recent studies).

Overall quality of evidence

Much of the knowledge on endometriosis is based on concepts in early stages of evidence development or on sparse literature. Many studies include single hospital or clinic population samples with small total sample sizes and disproportionately representing patients presenting with infertility compared with endometriosis associated pain. 10

Beyond the limitations of the existing literature, fundamental problems with the diagnosis of endometriosis must be overcome before we can adequately define endometriosis, its prevalence, biologically and clinically informative sub-phenotypes, and its response to treatment and long term prognosis. 11 The lack of a non-invasive diagnostic modality creates insurmountable diagnostic biases driven by characteristics of those patients who can and those who cannot access a definitive surgical or imaging diagnosis and at what point in their endometriosis journey the condition is diagnosed.

Ovarian endometrioma or deep endometriosis can be diagnosed through imaging if the patient is geographically, economically, and socially able to achieve referral to and evaluation from an experienced imaging specialist. 12 13 For women with superficial peritoneal disease, definitive diagnosis by means of surgical evaluation is limited to those with symptoms deemed sufficiently severe and life affecting and resistant to empiric treatment to justify the inherent risks of surgery. Even among patients with symptoms deemed to have enough of an effect to warrant referral for a surgical evaluation, stigma, 14 disbelief and misperceptions of pain or fertility that can be driven by racism or elitism, 15 and geographic and economic barriers to accessing endometriosis focused surgeons remain.

Beyond access to an appropriate, skilled physician, the wide range of symptoms associated with endometriosis—many of which are stigmatized or normalized 14 16 —reduces the likelihood of referral and increases time to referral to appropriate specialists. 5 6 11 17 The bias in diagnosis itself may be influenced by variations in clinical symptoms among different populations not adequately captured or appreciated by standard clinical definitions or may represent implicit bias in healthcare, leading to an alternate interpretation of the same symptoms affecting the likelihood of diagnosis. This delay to diagnosis affects patients directly, but it also results in most scientific studies capturing patients’ characteristics, biologic samples, and biomarker measurements far into the natural pathophysiologic progression of the disease. Moreover, studies from African and Asian countries are considerably under-represented compared with European and North American countries. 10 High quality studies from these regions and development of a sensitive non-invasive diagnostic tool might alter existing global prevalence and incidence estimates and may reveal a more comprehensive view of what early milieu, signs and symptoms, and long term health outcomes are truly attributable to endometriosis.

Definition, symptoms, and classification

Among women with the condition, endometriosis has a highly heterogeneous presentation of visualized endometriotic lesions, multisystem symptom presentation, and comorbid conditions ( fig 1 ).

Highly varied presentation of endometriosis

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Surgically visualized macro sub-phenotypes of endometriosis

Endometriosis is defined by the presence of endometrium-like epithelium and/or stroma (lesions) outside the endometrium and myometrium, usually with an associated inflammatory process. 18 Most endometriosis is found within the abdominal cavity, and it exists as three subtypes: superficial peritoneal endometriosis (accounting for around 80% of endometriosis), ovarian endometriosis (cysts or “endometrioma”), and deep endometriosis 1 19 ( box 1 ; fig 2 ). All forms of endometriosis can be found together, not solely as separate entities. Although not a subtype, endometriosis situated inside the bowel wall is termed “bowel endometriosis.” It mostly affects the rectosigmoid area, but lesions can also be found in other parts of the gastrointestinal system, including the appendix. Endometriosis involving the detrusor muscle and/or the bladder epithelium is termed “bladder endometriosis.” Extra-abdominal (replacing the older term “extra-pelvic”) endometriosis is used to describe any endometriosis lesions found outside of the abdomen (for example, thoracic endometriosis). 20 Iatrogenic endometriosis describes endometriosis thought to be arising from direct or indirect dissemination of endometrium following surgery (for example, cesarean scar endometriosis).

Nomenclature 18

Superficial peritoneal endometriosis.

Endometrium-like tissue lesions involving the peritoneal surface with multiple appearances

Ovarian endometriosis

Endometrium-like tissue lesions in the form of ovarian cysts containing endometrium-like tissue and dark blood stained fluid (endometrioma or “chocolate cysts”)

Deep endometriosis

Endometrium-like tissue lesions extending on or infiltrating the peritoneal surface (usually nodular, invading into adjacent structures, and associated with fibrosis)

Extra-abdominal endometriosis

Endometrium-like tissue outside the abdominal cavity (for example, thoracic, umbilical, brain endometriosis)

Iatrogenic endometriosis

Direct or indirect dissemination of endometrium following surgery (for example, cesarean scar endometriosis)

Surgical images of endometriosis sub-phenotypes

Adenomyosis is not a sub-phenotype of endometriosis, 21 although it is characterized by endometrial tissue surrounded by smooth muscle cells within the myometrium. 22 Symptoms include dysmenorrhea and heavy menstrual and/or abnormal uterine bleeding, 23 and a heterogeneous adenomyosis presentation is visualized with radiologic imaging or at hysterectomy that lacks an agreed terminology or classification system. 24 25 Evidence is emerging of tissue injury and repair mechanisms mediated by estradiol and inflammation. 25 26

Endometriosis associated symptoms

Endometriosis is often associated with a range of painful symptoms that include chronic pelvic pain (cyclical and non-cyclical), painful periods (dysmenorrhea), painful sex (dyspareunia), and pain on defecation (dyschezia) and urination (dysuria). 1 27 Their severity can range from mild to debilitating. Some women have no symptoms, others have episodic pelvic pain, and still others experience constant pain in multiple body regions. 28 A related observation is that some women transition between these categories, progressing from episodic and localized pain to that which is chronic, complex, and more difficult to treat. Furthermore, women with disease that is anatomically “severe” can have minimal symptoms and women with “minimal” evidence of endometriosis can have severe, life affecting symptoms. 1 19 In common with other chronic pain conditions, women with endometriosis often report experiencing fatigue and depression. Infertility is significantly more common in patients with endometriosis, with a doubling of risk compared with women without endometriosis. 2 Endometriosis is discovered in 30-50% of women who present for assisted reproductive treatment. 29 30

Endometriosis associated or high risk comorbidities

Endometriosis is certainly a multisystem condition, perhaps as a result of common pathogenesis or as a consequence of the chronic endogenous response to the presence of endometriotic lesions. 9 Although pelvic pain is the most common symptom of possible endometriosis, women with endometriosis also have a high risk of co-occurring or evolving multisite pain. 28 Patients with endometriosis have a higher risk of presentation with comorbid chronic pain conditions such as fibromyalgia, 31 32 33 migraines, 34 35 and also rheumatoid arthritis, 33 36 psoriatic arthritis, 37 and osteoarthritis. 36 38 Reports of back, bladder, or bowel pain are prevalent, 16 39 with dyschezia being potentially predictive of endometriosis. 40 Nearly 50% of women with bladder pain syndrome or interstitial cystitis have endometriosis. 41 42 Irritable bowel syndrome is a common co-occurring diagnosis that reinforces the importance of awareness of endometriosis among gastroenterologists. 43 44 45 These conditions may share a common cause, 46 they may arise together owing to shared environmental or genetic factors, and/or the occurrence of comorbid pain conditions could be due to changes in pain perception after repeated sensitization. 47 Research focused on disentangling the overlapping and independent pathways of these frequently co-occurring pain associated conditions is essential. 48 49

Women with endometriosis have a greater risk of presenting with other non-malignant gynecologic diseases, including uterine fibroids and adenomyosis. 50 51 They are also at greater risk of a subsequent diagnosis of malignancies, autoimmune diseases, early natural menopause, and cerebrovascular and cardiovascular conditions. 36 52 53 54 55 56 57 The hypothesized causal mechanisms for endometriosis discussed below are all thought to be enhanced by and/or result in chronic inflammation. Local and systemic chronic inflammation can directly activate afferent nociceptive fibers and promote pelvic pain, 58 although this does not entirely explain the heterogeneity in types and severity of painful symptoms that patients experience. Furthermore, endometriosis induced chronic inflammation and immune dysregulation may also contribute to the endometriosis associated subsequent risk of each of these comorbid conditions. 59 60

Although this multisystem effect reinforces the importance of knowledge of and attention to endometriosis from general practitioners and a myriad specialists for whole healthcare, the most prominent association, and the focus of the greatest volume of comorbidity research, is the elevated risk of ovarian cancer among women with endometriosis. A recent meta-analysis confirmed this association, 53 finding a nearly twofold greater relative risk of ovarian cancer among patients with endometriosis (summary relative risk (SRR) 1.93, 95% confidence interval 1.68 to 2.22; n=24 studies) that was strongest for clear cell (3.44, 2.82 to 4.42; n=5 studies) and endometrioid (2.33, 1.82 to 2.98; n=5 studies) histotypes. However, among these 24 studies, significant evidence existed of both heterogeneity across studies and publication bias (Egger’s and Begg’s P values <0.01). Clinicians need to reinforce that ovarian cancer is rare regardless of women’s endometriosis status 61 : the absolute lifetime risk in the general population is 1.3%, 62 and applying the risk estimate from the meta-analysis (SRR 1.9) gives an absolute lifetime risk for women with endometriosis of 2.5%, which is 1.2% higher than the absolute risk for women without endometriosis and still very low.

We should also recognize that coexisting gynecologic conditions such as adenomyosis and uterine fibroids, 50 as well as associations with endometrial cancer, 53 can be influenced by diagnostic biases and failure to distinguish between diagnoses in women undergoing hysterectomy and those in women with an intact uterus. 11 51 When attempting to infer a causal relation between endometriosis and other conditions, applying rigorous prospective temporality (rather than cross sectional co-occurrence) is particularly important for valid subsequent risk associations. 53 These studies need large study populations with well documented longitudinal data. A large impediment is the lack of routine, harmonized documentation of the characteristics of endometriosis and its absence from international classification of diseases coding. 63 64

Endometriosis classification systems

Several classification, staging, and reporting systems have been developed; 22 systems were published between 1973 and 2021. 65 The three most commonly used systems are the revised American Society for Reproductive Medicine (rASRM) classification (stages I-IV; where stage I is equivalent to “minimal” disease and stage 4 to “severe” disease), the ENZIAN (and newer #ENZIAN) classification, and the Endometriosis Fertility Index (EFI). 66 67 68 69 Many validation studies and reports on the implementation of the different systems have been published. The rASRM system (scored at surgery on the basis of the extent of visualized superficial peritoneal lesions, endometriomas, and adhesions) has been shown to have poor correlation with pain, 70 fertility outcomes, and prognosis, and the ENZIAN system (which additionally includes deep endometriosis) has been shown to have poor correlation with symptoms and infertility. 71 72 73 The EFI is a well validated clinical tool that predicts pregnancy rates after surgical staging of endometriosis, with ongoing evaluation to determine the predictive importance of the individual parameters included in the scoring algorithm as well as the effect of completeness of surgical treatment on pregnancy prediction. 74 Unfortunately, no international agreement exists on how to describe endometriosis or how to classify it. As most systems show no, or very little, correlation with patients’ symptoms and outcomes, this is further evidence of our lack of understanding of the physiology underlying the symptoms associated with endometriosis.

Epidemiology

The exact prevalence of endometriosis is unknown given diagnostic delays and barriers, and—perhaps consequently—it is extremely varied depending on the population and the indication for evaluation. A recent meta-analysis identified 69 studies describing the prevalence and/or incidence of endometriosis, among which 26 studies were general population samples, 17 were from regional/national hospitals or insurance claims systems, and the remaining 43 studies were conducted in single clinic or hospital settings. 10 The prevalence reported in general population studies ranged from 0.7% to 8.6%, whereas that reported in single clinic or hospital based studies ranged from 0.2% to 71.4%.

When defined by indications for diagnosis, the prevalence of endometriosis ranged from 15.4% to 71.4% among women with chronic pelvic pain, from 9.0% to 68.0% among women presenting with infertility, and from 3.7% to 43.3% among women undergoing tubal sterilization. Few studies have investigated the incidence and prevalence of endometriosis specifically among adolescents. The reported prevalence of visually confirmed endometriosis among adolescents with pelvic pain ranges from 25% to 100%, with an average of 49% among adolescents with chronic pelvic pain and 75% among those unresponsive to medical treatment. 75 The Ghiasi meta-analysis reported a decrease in recorded prevalence across the past 30 years. 10 Speculating, this may be due to more rapid and more ubiquitous embracing of empiric treatment of symptom, forgoing or delaying definitive imaging or surgical diagnosis, a patient centered approach that has been ratified by the most recent European endometriosis guideline. 13 This hypothesis is supported by a recent report from a large US health system’s electronic medical records database that observed a decline from 2006 through 2015 in incidence rates for endometriosis (from 30.2 per 10 000 person years in 2006 to 17.4 per 10 000 person years in 2015) but an increase in documentation of chronic pelvic pain diagnoses (from 3.0% to 5.6%). 76

Pathophysiology

Heritability and genetics.

Estimates from twin studies suggest 47-51% total heritability of endometriosis, with 26% estimated to be from genetic variation. 77 78 79 To date, nine genome-wide association studies have been reported. 59 The largest study so far, using 17 045 cases and 191 596 controls, has identified 19 single nucleotide polymorphisms, most of which were more strongly associated with rASRM stage III/IV, rather than stage I/II, explaining 1.75% of risk for endometriosis. 80 Consistent with other complex diseases with multifactorial origins, no high penetrance susceptibility genes for endometriosis have yet been identified. 62 The loci discovered to date are almost all located in intergenic regions that are known to play a role in the regulation of expression of target genes yet to be identified. The critical next steps in genetic discovery are to identify additional genes that reveal novel pathophysiological pathways and also emerge to better define the underpinnings of variation in symptoms (in particular, pain types and infertility and treatment response predictors) and also gene expression correlated with comorbid autoimmune, cancer, and cardiovascular conditions. 62

Reflux of endometrial tissue fragments/cells and protein rich fluid through the fallopian tubes into the pelvis during menstruation is considered the most likely explanation for why endometriotic lesions form within the peritoneal cavity, although this mechanism is not sufficient as nearly all women experience retrograde menstruation. 81 82 Additional postulated origins include celomic metaplasia and lymphatic and vascular metastasis. Scientific avenues exploring contributions of interacting endocrine, immunologic, proinflammatory, and proangiogenic processes are drawing curiosity and expertise from varied disciplines with application of state of the art technologies. 59 Retrograde menstruation of stem cells contributes to the establishment of endometriosis, 83 whereas bone marrow stem cells contribute to the continued growth of endometriosis lesions. 84 85 Bone marrow derived stem cells may be responsible for those cases of endometriosis outside of the abdominal cavity. 86

Studies exploring why lesions develop in some, but not all, women have detected changes in the endometrial tissue as well as in the peritoneal fluid and cells lining the cavity. Eutopic endometrial tissue has a significantly different immune profile in women with endometriosis compared with those without it. 87 However, the extent to which this inflammation is a cause or an effect of endometriosis remains unclear. Aberrant inflammation could have an effect on the development of endometriosis lesions and disease progression in various ways, including immune angiogenesis and immune-endocrine interaction. 59 60 Specifically, some of the proposed pathways include altered production of inflammatory cytokines by immune cells in lesions or by endometrial cells themselves involving decreased immune clearance of abnormal endometrial cells and consequent seeding and development of lesions, increased likelihood of adhesion to mesothelial cells due to pro-invasion inflammatory milieu, inflammation promoted proliferation of endometrial cells, and inflammation promoted reduction in apoptosis of endometrial cells. 88 Analysis of eutopic endometrium from women with endometriosis has identified altered expression of genes implicated in the inflammation/immune response, angiogenesis, and steroid responsiveness (progesterone “resistance”). 89 Shed menstrual tissue contains high concentrations of pro-inflammatory cytokines, proteases, and immune cells, all of which may influence the peritoneal microenvironment after reflux. Stem/progenitor cells have been identified in the endometrium and are thought to survive and implant onto the peritoneum, contributing to lesions. 83 Mesothelial cells line the pelvic peritoneal cavity, and changes in their function in women with endometriosis, including altered morphology and metabolism (switch to aerobic glycolysis) 90 and production of factors that promote immune cell recruitment and angiogenesis are all thought to favor survival and establishment of lesions. 91 Physiological hormonal fluctuations in women induce cyclical episodes of cell proliferation, inflammation, injury, and repair within lesions that favor fibroblast to myofibroblast differentiation and fibrosis.

Mechanisms of endometriosis associated pain

The development of a new blood supply and associated nerves (neuroangiogenesis) is considered key to the establishment of endometriotic lesions and the activation of peripheral pain pathways ( fig 3 ). 92 Sensory C, sensory Ad, cholinergic, and adrenergic nerve fibers have all been detected in lesions. Estrogens can promote crosstalk between immune cells and nerves within lesions, increasing expression of nociceptive ion channels such as the transient receptor potential cation channel subfamily V member 1. 93 Factors that promote inflammation and nerve growth, such as nerve growth factor, tumor necrosis factor α, and interleukin 1-β, are increased in the peritoneal fluid of women with endometriosis and may exacerbate a neuroinflammatory cascade. Consistent with other conditions associated with chronic pain, endometriosis is associated with unique, and sometimes disease specific, alterations in the peripheral and central nervous systems, including changes in the volume of regions of the brain and in brain biochemistry. 94 Increased risk of central sensitization may partially explain why approximately 30% of patients with endometriosis will develop chronic pelvic pain that is unresponsive to conventional treatments, including surgery. 95 Through this central process, patients can experience reduced pain thresholds, increased responsiveness and length of aftereffects to noxious stimuli, and expansion of the receptive field so that input from non-injured tissue may elicit pain. 46 47 Among endometriosis patients with central sensitization, the removal of the endometriotic lesions is unlikely to result in adequate pain remediation owing to continued activation of the central nervous system. 96 97 Thus, endometriosis associated pain does not neatly fall into one of the three main categories of chronic pain (that is, nociceptive, neuropathic, or nociplastic), 98 99 100 and it likely has a mixed pain phenotype or sits somewhere along a continuum of these pain phenotypes. For example, some patients have primarily nociceptive or neuropathic pain, others have primarily nociplastic pain, and the rest have a mixed phenotype with variable contributions of nociceptive, neuropathic, and nociplastic pain.

Pathophysiology of endometriosis: (1) potential factors contributing to endometriosis associated pain; (2) potential mechanisms of endometriosis associated infertility; (3) local factors involved in the development of an endometriosis lesion; (4) role of the eutopic endometrium in the development of an endometriosis lesion. CNS=central nervous system; PNS=peripheral nervous system

Mechanisms of endometriosis associated infertility

Endometriosis may impair fertility through multiple pathways, including peritoneal inflammation and endocrine derangements, which interfere with the follicular environment and consequently affect ovarian function and ultimately reduce oocyte competence. 101 Several studies of women undergoing in vitro fertilization have documented lower oocyte yield or ovarian reserve among women with endometriosis compared with those with other infertility diagnoses. 102 103 A recent study observed lower oocyte yield among endometrioma affected ovaries but not among the contralateral ovaries that were unaffected by endometriosis compared with unexposed ovaries from women with no evidence of endometriosis. 104 In addition, although unproven, anatomical distortion and adhesions caused by endometriosis, particularly in stage III-IV disease, seem likely to reduce the chance of natural conception.

No way to prevent endometriosis is known. Enhanced awareness, followed by early diagnosis and management, may slow or halt the natural progression of the disease and reduce the long term burden of painful symptoms, including possibly the risk of central sensitization, but no cure exists. Furthermore, the evidence for modifiable risk factors for endometriosis remains unacceptably sparse. 12 Critically needed are large scale longitudinal studies that can quantify modifiable exposures in girls and young women in the pre-diagnostic, and ideally the pre-symptomatic, window that are then explored further in humans, 105 106 107 as well as in experimental models, to determine the physiologic pathways defined by causal effects on the epigenome, transcriptome, proteome, and metabolome. To date, few risk factors have been robustly replicated in multiple populations, with the most consistently associated with endometriosis including müllerian anomalies, low birth weight and lean body size, early age at menarche, short menstrual cycles, and nulliparity. 1 11 Less research has supported associations with endocrine disrupting toxins including diethystilbestrol. 108

Clinical course

A critical aspect of care for women with endometriosis is that associated symptoms progress and recede over the life course, sometimes in response to treatment and sometimes with age or altered environment in pathways that we do not yet understand ( fig 4 ). For example, pain remediation is often a priority among adolescents, 109 whereas older women may be focused on fertility or on life affecting fatigue. 8 110 Furthermore, a long held belief that endometriosis and its symptoms do not occur in adolescents and end at menopause was erroneous. However, the years of perimenopause can be a time of increased pelvic pain, 111 112 with particular attention needing to be paid to symptom management that may include an unexpected return of pain in those patients for whom a treatment regimen had been successful during premenopause. 113 Clinicians need to focus across the life course on patient centered care, engaging in a dialogue to capture evolving symptomatology but also to collaborate on what symptoms are of most importance to the patient at this life stage. 110 Importantly, all that we believe we know about endometriosis is limited to the characteristics and natural history of those women who successfully obtain a diagnosis. To whatever extent asymptomatic or incidental findings have influenced the diagnostic population or to whatever extent health disparities or biases regarding symptom belief or access to pain or infertility care have limited or skewed those diagnosed, our elucidation of the true signs and symptoms and prognosis of endometriosis will evolve as care and access to it improves. 11

Endometriosis risk, establishment, and multisystem effects encompassing evolution across the life course

Diagnosis and monitoring

Although endometriosis has a highly variable presentation, steps can be recommended for decision making by general practitioners and gynecologists to approach a “working diagnosis” of probable endometriosis, implement treatment to remediate endometriosis associated symptoms, and consider multi-specialty collaboration for patient centered whole healthcare ( fig 5 ).

Flowchart for a step-by-step approach to patients with suspected endometriosis (adapted from flowcharts in the NICE 114 and ESHRE 13 endometriosis guidelines). *Imaging does not rule out endometriosis; if “negative” imaging but symptoms highly suggestive of endometriosis, consider “working diagnosis” of probable endometriosis. †General practitioners should monitor for emergence of signs of conditions associated with endometriosis and involve/refer to appropriate specialist (eg, gastroenterologist, cardiologist, rheumatologist, psychologist, oncologist). ‡Ideally within accredited specialist endometriosis center

“Red flag” symptoms and signs

The diagnosis of endometriosis should be considered in women (including girls aged 17 and under) presenting with one (or more) of the following symptoms or signs: chronic pelvic pain with or without cyclic flares, dysmenorrhea (affecting daily activities and quality of life), deep dyspareunia, cyclical gastrointestinal symptoms (particularly dyschezia), cyclical urinary symptoms (particularly hematuria or dysuria), or infertility in association with one (or more) of the preceding symptoms or signs. 114 Shoulder tip pain (pain under the shoulder blade), catamenial pneumothorax, cyclical cough/hemoptysis/chest pain, and cyclical scar swelling/pain can indicate endometriosis at extra-abdominal sites. 13 40 115 116 Fatigue is commonly reported by women with endometriosis. An abdomino-pelvic examination may help to identify ovarian and deep disease. 117

Diagnostic biomarkers

Many research studies and Cochrane reviews have assessed potential biomarkers for endometriosis, 118 119 120 with the ultimate goal of reducing the delay that exists in diagnosing endometriosis. Unfortunately, all of the candidates investigated to date have proven non-specific or unreliable, making them inappropriate for routine clinical use.

Imaging to diagnose endometriosis

Ultrasonography and magnetic resonance imaging (ideally two dimensional, T2 weighted sequences without fat suppression) can be used to diagnose endometriosis preoperatively, but the absence of findings on imaging does not exclude endometriosis, particularly superficial peritoneal disease. 121 122 Nevertheless, the ENDO Study enrolled 131 women from the general population who had not presented for gynecologic evaluation, among whom magnetic resonance imaging was used to diagnose endometriosis in 11%. 123 Although the sensitivity of transvaginal ultrasonography is maximized only for endometriomas, technological and training advances are improving detection of all sub-phenotypes of endometriotic lesions. 124 125 Saline infusion sonoPODography is a novel technique that may be able to diagnose superficial peritoneal endometriosis on ultrasonography, although it needs to be validated. 126

Laparoscopic diagnosis and appearance of endometriosis

In patients with suspected endometriosis, in whom imaging has shown no obvious pelvic pathology or for whom empirical treatment has been unsuccessful, laparoscopy is recommended for diagnosis. Laparoscopy for endometriosis should always involve a comprehensive exploration of the abdominal and pelvic contents. Histopathological confirmation is ideal; however, histologic definitions for endometriosis have remained stagnant for decades, with a lower than expected sensitivity, 12 particularly among younger women with endometriosis. 127 Superficial peritoneal endometriosis has been described as having a black (powder burn) or dark bluish appearance from the accumulation of blood pigments ( fig 2 ). 128 However, lesions can appear as white opacifications, red flame-like lesions, or yellow-brown patches in earlier, active stages of disease. 129 Ovarian endometriomas have a distinct morphology classically described as a “chocolate cysts,” containing old menstrual blood, necrotic fluid, and other poorly defined components that give their contents a dark brown appearance. Adhesions are often found in association with endometriomas and consist of fibrous scar tissue resulting from chronic inflammation. In many cases, endometriosis is present at the site of ovarian fixation. 130 Deep endometriosis appears as multifocal nodules and may infiltrate the surrounding viscera and peritoneal tissue. 131 Almost 40% of laparoscopies done for pelvic pain do not identify any pathology. 99 Clinicians should always consider other pelvic and non-pelvic visceral and somatic structures, as well as centrally mediated pain factors, that could be generating or contributing to the pain. 99

“Working diagnosis” of probable endometriosis

In women with a high suspicion of endometriosis, in whom imaging has not shown obvious pelvic pathology and a laparoscopy has not been done or is awaited, giving a “working diagnosis” of probable endometriosis and instigating early medical treatment without waiting for a more definitive diagnosis can be helpful. 13 114 132 133 This is an emerging concept for which some people use the terms “working” and “clinical” diagnosis interchangeably.

Delayed diagnosis

Endometriosis can occur at any age, with some patients reporting that pelvic pain symptoms arose at or soon after thelarche or menarche. Among women with endometriosis diagnosed in adulthood, nearly a fifth report that their symptoms began before age 20 and two thirds report onset before age 30. 5 The exact time of disease onset is unknown for endometriosis, as symptoms must emerge and be sufficiently life affecting to gain referral for definitive diagnosis. Furthermore, non-specific symptoms such as dysmenorrhea have often been treated with hormonal drugs without consideration of endometriosis, whereas the current recommendation is to be aware and consider a working diagnosis of probable endometriosis. Thus, varied non-specific symptomatology, normalization of pelvic pain, clinicians’ awareness of endometriosis, and economic and geographic access to care all contribute to a delay averaging seven years from symptom onset to surgical diagnosis. 1 5

Long term monitoring of endometriosis

Follow-up, including psychological support, should be considered in women with confirmed endometriosis, with renewed evaluation and a revised treatment plan if symptoms emerge, recur, or worsen over time. However, no evidence exists of benefit of regular long term monitoring (for example, imaging) for early detection of endometriotic lesion recurrence, complications, or malignant transformation, in the absence of complex ovarian masses or endometriosis with deep bowel effect. 134 135 Given growing evidence of risk of multisystem involving conditions ( fig 4 ), patient centered whole healthcare dictates that monitoring by general practitioners for emergence of signs and symptoms of mental health conditions, cardiovascular disease, immunologic and autoimmune disorders, gastrointestinal conditions, or multifocal pain conditions should be heightened and referral to a non-gynecologic specialist should be considered as needed.

Management of endometriosis associated pain

The growing recognition that endometriosis associated pain has a mixed pain phenotype (or occupies different points on a continuum) supports a personalized, multimodal, interdisciplinary treatment approach, 13 which might include surgical ablation/excision of lesions, analgesics, hormonal treatments, non-hormonal treatments including neuromodulators, and non-drug therapies (or a combination of the above). 1 The evidence supporting different surgical, pharmacologic, and non-pharmacologic approaches to treating endometriosis is examined below.

Surgical management of endometriosis associated pain

The most recent guidelines for endometriosis (for example, the National Institute for Health and Care Excellence (NICE), ESHRE) recommend surgery as a treatment option to reduce endometriosis associated pain. 13 114 However, only a limited number of RCTs have assessed pain outcomes after surgery (and most are small, offer little detail on endometriosis sub-phenotypes visualized at surgery, and have a follow-up period of less than 12 months). Furthermore, the authors of the most recent Cochrane review of surgery for endometriosis associated pain concluded that they were “uncertain of the effect of laparoscopic surgery on pain and quality of life” owing to the low quality of the available studies. 136 They included only two of the published RCTs (comparing surgical treatment of endometriosis with diagnostic laparoscopy alone) in their analysis of laparoscopic excision to improve pain and quality of life. 137 138 One trial of 16 participants experiencing pain associated with endometriosis assessed “overall pain” scores at 12 months (mean difference on 0-100 visual analog scale (VAS) 1.65, 95% confidence interval 1.11 to 2.19), and the other trial of 39 participants assessed quality of life at six months measured using the EuroQol-5D (mean difference 0.03, –0.12 to 0.18). The evidence of benefit for specific subtypes is discussed in more detail below.

Surgery for superficial peritoneal endometriosis

Little evidence shows that surgery to treat isolated superficial peritoneal endometriosis improves overall symptoms and quality of life. The uncertainty around surgical management of this subtype is compounded by the limited evidence to allow an informed selection of specific surgical modalities to remove the lesions (for example, laparoscopic ablation versus laparoscopic excision). 139 140

Surgery for ovarian endometriosis

To our knowledge, no RCTs have compared cystectomy versus no treatment in women with endometrioma and measured the effect on painful symptoms. Also, no published data indicate a threshold cyst size below which surgery may be safely withheld in the absence of suspicious features on imaging (surgery is the only means by which a tissue specimen can be obtained to rule out ovarian malignancy). Thus, surgical excision is generally considered the optimal treatment for ovarian endometriosis. Cystectomy, instead of drainage and coagulation, is the preferred surgical approach as it reduces recurrence of endometrioma and endometriosis associated pain. 141 Cystectomy should be chosen with caution for women who desire fertility, as a risk of fertility affecting diminished ovarian reserve exists, and a highly skilled conservative approach should be applied to minimize ovarian damage. 142

Surgery for deep endometriosis

Surgical treatment to completely excise deep disease is generally considered to be the treatment of choice. 143 144 Nevertheless, most of the studies that have reported improvements in quality of life following surgical excision of deep endometriosis (typically involving the bowel) have been done in small cohorts of women, usually from single centers, without a comparator arm, and this affects the precision and generalizability of the results. The largest multicenter prospective non-randomized study published to date reported the six, 12, and 24 month follow-up outcomes on nearly 5000 women undergoing laparoscopic excision of deep rectovaginal endometriosis. 143 This showed clinically and statistically significant reductions in premenstrual, menstrual, and non-cyclical pelvic pain, deep dyspareunia, dyschezia, low back pain, and bladder pain at 24 months (data from 524-560 participants for each symptom) with a corresponding improvement in quality of life (575 participants, median score on EuroQol-5D 76, 95% confidence interval 75 to 80). Although the results should be interpreted with caution, because data were missing for >70% of patients at 24 months, assigned score methods suggest that evidence of improvement remained statistically significant.

Hysterectomy for endometriosis

No RCTs on hysterectomy for the treatment of endometriosis associated pain have been done. Most published articles are retrospective case series, and only a few prospective studies have been reported. Hysterectomy (with or without oophorectomy) with removal of all visible endometriosis lesions should be reserved for women who no longer wish to conceive and who have not responded to more conservative management. Women with endometriosis should be informed that hysterectomy is not a “cure” for endometriosis and that it is best reserved for women with coexisting adenomyosis (which does occur inside the uterus) or for women with severe pain who have exhausted all other options to improve their symptoms. 145 Recent longitudinal studies have not found a benefit of bilateral oophorectomy for long term pain management. 145 146 Of note, BIPOC (black, indigenous, and people of color) women are more likely to have complications of hysterectomy, in part because they are more likely to undergo laparotomy rather than minimally invasive laparoscopy. 147 Women should be informed that hysterectomy is associated with long term morbidity, 148 including cardiovascular disease, 56 among those with and without surgically induced menopause. 149 150

Recurrence or progression of endometriosis after surgery

The reported recurrence rate of painful symptoms attributed to endometriosis is high, estimated as 21.5% at two years and 40-50% at five years. 146 151 However, although a purist’s definition of “endometriosis recurrence” calls for “second look” laparoscopy, it is most often diagnosed in the real world on the basis of recurrence of symptoms alone. In addition, no robust evidence exists to support an ordered progression of endometriotic lesions. In prospective studies of repeat surgeries, lesions progressed (in 29% of cases), regressed (in 42%), or were static (in 29%). 152 Surgical treatment of certain subtypes of endometriosis could also exacerbate painful symptoms. 153 154

Preoperative and postoperative hormone treatment

Preoperative hormone treatment has not been shown to improve the immediate outcome of surgery for pain, or reduce recurrence, in women with endometriosis. 155 A meta-analysis of 340 participants found that compared with surgery alone, postoperative hormone treatment of endometriosis reduced pelvic pain after 12 months (standardized mean difference on VAS −0.79, −1.02 to −0.56), but the evidence is very low quality. 155 Women with endometriosis who undergo hysterectomy with oophorectomy should be advised to start continuous combined hormone replacement therapy (HRT) for at least the first few years after surgery. 156 This may be changed later to estrogen alone, but this needs to be balanced with the theoretical risk of reactivation and malignant transformation of any residual endometriosis, which can occur many years later.

Pharmacologic management of endometriosis associated pain

Most women with suspected or known endometriosis use over-the-counter drugs, such as non-steroidal anti-inflammatory drugs (NSAIDs). However, the available evidence to support their use is scarce. The data on the benefit of NSAIDs are limited to one small RCT. 157 They can be useful as “breakthrough medication” in the management of a pain flare.

Hormonal treatments

Hormone treatments for endometriosis include combined contraceptives, progestogens, gonadotrophin releasing hormone (GnRH) agonists, GnRH antagonists, and aromatase inhibitors ( table 1 ). All of these hormone treatments (except the newer GnRH antagonists, which have not been so extensively studied) have been included in a multivariate network meta-analysis of the outcomes “menstrual pain” and “non-menstrual pelvic pain” (pain relief on VAS; total of 1680 participants). 114 All treatments led to a clinically significant reduction in pain on the VAS compared with placebo. The magnitude of this treatment effect is similar for all treatments, suggesting that little difference exists between them in their capacity to reduce pain. Furthermore, symptoms return after cessation of treatment and hormone treatments used to manage endometriosis all have side effects. In addition, although the contraceptive properties of the hormones may be welcome if the woman does not wish to become pregnant, they may be unwanted if fertility is desired.

Hormone treatments

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Non-hormonal treatments

Analgesic tricyclic antidepressants (for example, amitriptyline, nortriptyline), selective serotonin uptake inhibitors (for example, duloxetine) and anticonvulsants (for example, gabapentin and pregabalin) are sometimes used clinically in the treatment of endometriosis associated pain without a strong evidence base. 167 These “neuromodulatory drugs” differ from conventional analgesics, such as NSAIDs, in that they primarily affect the central nervous system’s modulation of pain rather than peripheral mediators of inflammation. However, in a recent RCT for the management of chronic pelvic pain (in the absence of endometriosis), gabapentin was not shown to be superior to placebo and was associated with dose limiting side effects. 168

Non-drug management of endometriosis associated pain

Pelvic physiotherapy.

An increasing number of women with endometriosis report anecdotal benefit from pelvic physiotherapy. Physiotherapists may support women with activity management (for example, exercises, pacing strategies, and goal setting) and/or use complementary approaches to manage their pelvic pain symptoms (for example, massage and trigger point release therapy). Establishing the independent benefit of standalone physiotherapy is difficult, because most studies have assessed it in combination with psychological and medical management. 169 Two small pilot studies assessed the outcome of manipulations and massage for relief of endometriosis associated pain specifically, but they included specific patient groups and need expansion and replication to support recommendations for care of endometriosis patients. 170 171

The most common psychologically based intervention for chronic pain is cognitive behavioral therapy (CBT). Most of the studies of CBT in women with endometriosis are of low quality, designed using different methods and based on different psychological frameworks (making separation of effects difficult). However, given that CBT has been evaluated across a spectrum of other chronic pain disorders and shown to be effective for developing pain coping strategies, 98 99 172 it should be integrated into individualized treatment plans when needed.

Dietary intervention

Diet has been postulated to affect symptoms of endometriosis. However, very few studies (all of limited quality) have evaluated the benefit of dietary interventions and their effect on endometriosis symptoms. Supplements, such as omega-3 polyunsaturated fatty acids (O-PUFAs), have been investigated as a way of reducing inflammation and pain in endometriosis. 173 174 In a recent review, decreased pain scores were observed in women with endometriosis after use of O-PUFAs, which were not seen in controls. 175 Clinicians should be aware that women with endometriosis have an increased risk of co-presenting with irritable bowel syndrome concomitant with endometriosis associated dyschezia. 44 Patients are not uncommonly referred for gastroenterology evaluation without consideration of potential endometriosis. 45

Treatment of endometriosis associated infertility

Hormonal/medical therapies.

No evidence exists of benefit of suppression of ovarian function in women with endometriosis associated infertility who wish to conceive. 176 Following surgery for endometriosis, women seeking pregnancy should not be treated with postoperative hormone suppression with the sole purpose of enhancing future pregnancy rates.

Surgery to increase chance of natural pregnancy

Moderate quality evidence from a Cochrane meta-analysis of three RCTs in a total of 528 participants shows that laparoscopic treatment (ablation or excision) of superficial peritoneal endometriosis increases viable intrauterine pregnancy rates compared with diagnostic laparoscopy only (odds ratio 1.89, 95% confidence interval 1.25 to 2.86). 136 We found no data on live birth rates, and the effect on ectopic pregnancy and miscarriage rates is unclear. No published RCTs have assessed fertility outcomes after surgery for ovarian or deep disease, and surgery is generally recommended only in the presence of painful symptoms. 13 Use of the Endometriosis Fertility Index to support decision making for the most appropriate option to achieve pregnancy after surgery (for example, women who may benefit from medically assisted reproduction) has been recently suggested. 13 68

Medically assisted reproduction

Low quality evidence shows that viable intrauterine pregnancy rates are increased in women with superficial peritoneal endometriosis if they undergo intrauterine insemination with ovarian stimulation, instead of expectant management or intrauterine insemination alone. In one RCT of 103 participants randomized either to ovarian stimulation with gonadotrophins and intrauterine insemination treatment or to expectant management, the live birth rate was 5.6 (95% confidence interval 1.18 to 17.4) times higher in the treated couples. 177 In women with ovarian or deep endometriosis, the benefit of ovarian stimulation with intrauterine insemination is unclear. No RCTs have evaluated the efficacy of assisted reproductive technology (ART) versus no intervention in women with endometriosis. Recommendations in guidelines suggesting that ART may be effective for endometriosis associated infertility have been based on meta-analyses of observational studies comparing the outcomes of ART in women with and without endometriosis. 13 178 179 Doing surgery before ART for infertility associated with superficial peritoneal endometriosis is not recommended, as the evidence suggesting benefit is based on a single retrospective study of low quality 180 (and is not supported by indirect evidence from multiple studies comparing outcomes in women with surgically treated endometriosis and those managed without surgery 179 ). Doing surgery for ovarian endometrioma before ART to improve live birth rates is also not recommended. Current evidence shows no benefit, and surgery is likely to have a negative effect on ovarian reserve. 181 182 In addition, no evidence shows that doing surgical excision of deep endometriosis before ART improves reproductive outcomes, and this should be reserved for women with concomitant painful symptoms.

Specialist endometriosis centers

Specialist centers were first formally proposed in 2006, 183 and this model of care has been successfully implemented in the UK and several other European countries such as Denmark, Germany, and France. 184 185 The role of specialist endometriosis centers should be to offer a coordinated, holistic, multidisciplinary, multimodal approach to women with complex symptoms of endometriosis that are experienced and evolve across the life course ( fig 5 ). Although relevant surgical expertise is important, the role of a center is not to focus solely on surgical treatment to eradicate lesions. Thus, a specialist center should offer an integrated service, including gynecologists, colorectal surgeons, urologists, endometriosis specialist nurses, pain medicine specialists, psychologists, physiotherapists, fertility specialists, and imaging experts.

Various national and international organizations have issued guidelines for the assessment and management of endometriosis. We reviewed and compared nine of these guidelines (including the recent 2022 update of the ESHRE guideline). 186 187 188 189 190 191 192 193 All of the guidelines recommend the combined oral contraceptive pill and progestogens for endometriosis associated pain, but they differ in the recommendations around “second line” medical treatments. All of the guidelines recommend laparoscopic surgery for the management of endometriosis associated pain, although some acknowledge the lack of evidence for surgery in the management of pain associated with superficial peritoneal endometriosis specifically. 13 114 No clear consensus exists regarding surgical treatment for endometriosis associated infertility, especially with regard to the management of an endometrioma before assisted reproduction.

Emerging diagnostic tools and treatments

Most endometriosis research studies to date have been underfunded and on a small scale, and have involved poorly defined populations of women and samples captured from those who receive a diagnosis well along in their endometriosis journey. However, real hope exists of a breakthrough in the development of a biomarker to diagnose endometriosis closer to emergence and earlier in its natural progression, and to predict response to treatment, owing to the establishment of globally harmonized endometriosis protocols for clinical data and human tissue collection. 105 106 107 The biomarker field will also hopefully benefit from new insights being gained from the study of serum microRNAs and metabolomics. 194 195 Preclinical studies of new non-hormonal medical treatments have offered insights by focusing on inflammation, pain, and metabolism as the platform for repurposing of drugs already approved for other conditions. 19 90 196 Increasing evidence also suggests that the “gut-brain axis” could be a novel therapeutic target for pain symptom relief in endometriosis. 197 Microbiomes likely play a role in the gut-brain axis, are associated with the spectrum of symptoms associated with endometriosis, and are an exciting putative therapeutic target. Lastly, although randomized evaluations of surgical interventions for endometriosis have been rare (and some interventions have been adopted without rigorous evaluation), we are witnessing important collaboration between research and surgical communities to conduct large scale, appropriate, and well designed trials (for example, PRE-EMPT ( https://www.birmingham.ac.uk/research/bctu/trials/womens/pre-empt/index.aspx ), REGAL ( https://w3.abdn.ac.uk/hsru/REGAL/Public/Public/index.cshtml ), ESPriT2 ( https://www.ed.ac.uk/centre-reproductive-health/esprit2 ), and DIAMOND ( https://w3.abdn.ac.uk/hsru/DIAMOND/Public/Public/index.cshtml )). Surgical trials are difficult to undertake successfully and pose practical and methodological challenges. However, the inherent value of a well conducted RCT to predict the outcomes and/or success rates of surgical treatments for endometriosis should not be overlooked.

Endometriosis is a prevalent, often life affecting condition that in most women emerges during adolescence and can evolve to include symptoms and conditions encompassing multiple systems. Endometriosis demands to be known, considered, and tackled by all practitioners—general and specialist—who treat female patients at all stages across the life course. Patient centered whole healthcare requires a dialog between a woman and her healthcare practitioners to monitor symptom remediation, persistence, or recurrence and to prioritize the focus of care—for example, fatigue remediation when sports participation is paramount, fertility when family building is desired, a revision of medical treatment during perimenopause, or early response to signs of cardiovascular changes. Stigma around menstrual health and chronic pain remain all too ubiquitous barriers to high quality healthcare. Awareness in the general public and among healthcare providers is essential.

Once their symptoms are acknowledged and treated, most patients with endometriosis do well. However, despite overcoming diagnostic delays and access to state of the art treatment, some experience persistence or progression of symptoms. Critical next steps for discovery include defining sub-phenotypes of endometriosis that classify patients into groups that are predictive of prognosis and the natural course of the condition and indicate selection of treatments most likely to be successful to restore high quality of life. We must also answer foundational questions that remain about the causes and natural progression of endometriosis that need expanded funding and attraction of multidisciplinary scientists from all areas of population and bench science. Recommendations to permit a “working diagnosis” of probable endometriosis are having an effect on patient centered care and faster symptom remediation. Through the work of endometriosis associations, non-governmental organizations, and the endometriosis community across the globe, awareness of endometriosis has increased in recent years, along with some increases in funding. We are early on the necessary trajectory, but the journey is gaining speed.

Questions for future research

What causes endometriosis?

Can a non-invasive screening tool be developed to aid the diagnosis of endometriosis?

What are the most effective ways of maximizing and/or maintaining fertility in women with confirmed or suspected endometriosis?

What are the most effective ways of managing the emotional, psychological, and/or fatigue related impact of living with endometriosis?

Can we predict the outcomes and/or success rates for surgical or medical treatments for endometriosis?

What are the most effective non-surgical ways of managing endometriosis related pain and/or symptoms?

Adapted from the James Lind Alliance “Top ten research priorities for endometriosis in the UK and Ireland” 198

Patient involvement

We consulted Emma Cox, chief executive of Endometriosis UK, a nationally recognized representative and voice of patients with endometriosis, in the development of this review, and she commented on the draft and final manuscript. No patients were involved directly in the preparation of this article.

Acknowledgments

In addition to invaluable insight provided by Emma Cox, we thank Naoko Sasamoto and Marzieh Ghiasi for early design of figures 1 and 4, which were further adapted by SAM for this review; Kevin Kuan for designing figure 3 in BioRender; and Dan Martin for contributing image 1 to figure 2.

Series explanation: State of the Art Reviews are commissioned on the basis of their relevance to academics and specialists in the US and internationally. For this reason they are written predominantly by US authors

Contributors: AWH and SAM contributed equally to the planning, analysis, and writing of the article. AWH is the guarantor.

Funding: AWH is supported by an MRC Centre Grant (MRC G1002033) and an NIHR Project Grant (NIHR129801).

Competing interests: We have read and understood BMJ policy on declaration of interests and declare the following interests: AWH’s institution (University of Edinburgh) has received payment for consultancy and grant funding from Roche Diagnostics to assist in the early development of a possible blood diagnostic biomarker for endometriosis. AWH has received grant funding from the MRC and NIHR for endometriosis research; he is a board member of the World Endometriosis Society and Society for Endometriosis and Uterine Disorders, is co-editor in chief of Reproduction and Fertility , has been a member of the NICE and ESHRE Endometriosis Guideline Groups, and is a trustee and medical adviser to Endometriosis UK. SAM has received payment for consultancy and grant funding from AbbVie, LLC, for population based research unrelated to product development and has received grant funding from the US National Institutes of Health, US Department of Defense, and the Marriott Family Foundations for endometriosis research. SAM is a board member of the World Endometriosis Society, World Endometriosis Research Foundation, American Society for Reproductive Medicine Endometriosis Special Interest Group, and the European Society for Human Reproduction and Embryology Special Interest Group on Endometriosis and Endometrial Disorders; a member of the Interdisciplinary Network on Female Pelvic Health of the Society for Women’s Health Research; and is a statistical advisory board member for Human Reproduction and field chief editor for Frontiers in Reproductive Health .

Provenance and peer review: Commissioned; externally peer reviewed.

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Researchers identify genetic cause of endometriosis and potential drug target

Endometriosis is a painful, chronic condition in which tissue from the uterus inappropriately grows outside the uterus. 

Current treatments are limited and include surgery and hormone therapy, which can involve unwanted side effects. New research conducted by the University of Oxford, Baylor College of Medicine, the University of Wisconsin-Madison and Bayer AG, offers new insight into how to treat this debilitating disease.

The researchers performed genetic analyses of humans and rhesus macaques to identify a specific gene, NPSR1 , that increases risk of suffering from endometriosis. The results reveal a potential new nonhormonal drug target that may lead to improved therapy. Their results are published in Science Translational Medicine .

The Oxford team, led by Dr. Krina T. Zondervan, had previously found a genetic linkage to endometriosis on chromosome 7p13-15 by analysing DNA from families containing at least three women diagnosed with endometriosis. The Baylor team, led by Dr. Jeffrey Rogers, verified this genetic linkage in the DNA of rhesus monkeys with spontaneous endometriosis at the Wisconsin National Primate Research Center at the University of Wisconsin-Madison. This validation justified further research through in-depth sequencing analysis of the endometriosis families at Oxford, which narrowed down the genetic cause to rare variants in the NPSR1 gene.

Most of the women carrying these rare variants had stage III/IV disease. The Baylor researchers similarly sequenced rhesus monkeys and again showed suggestive evidence also in this species. Finally, an Oxford study of more than 11,000 women, including patients with endometriosis and healthy women, identified a specific common variant in the NPSR1 gene also associated with stage III/IV endometriosis.

Jeffrey Rogers, associate professor at the Human Genome Sequencing Center at Baylor, says: 'This is one of the first examples of DNA sequencing in nonhuman primates to validate results in human studies and the first to make a significant impact on understanding the genetics of common, complex metabolic diseases. The primate research really helped to provide confidence at each step of the genetic analysis in humans and gave us motivation to carry on chasing these particular genes.'

The insights revealed in this genetic analysis point to a potential new drug target. As part of this collaboration, researchers at Bayer, in scientific partnership with Oxford University, used an NPSR1 inhibitor to block protein signaling of that gene in cellular assays and then in mouse models of endometriosis. They found this treatment led to reduced inflammation and abdominal pain, thus identifying a target for future research in treating endometriosis.

Krina Zondervan, professor of reproductive and genomic epidemiology, head of the Department of Women’s and Reproductive Health at the University of Oxford and co-director of the Endometriosis CaRe Centre at Oxford says: 'This is an exciting new development in our quest for new treatments of endometriosis, a debilitating and underrecognized disease affecting 190 million women worldwide. We need to do further research on the mechanism of action and the role of the genetic variants in modulation of the gene’s effects in specific tissues.

'However, we have a promising new nonhormonal target for further investigation and development that appears to address directly the inflammatory and pain components of the disease.'

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Clinical Trials

Endometriosis.

Displaying 11 studies

The purpose of this study is to examine the gene expression within endometriosis.

The purpose of this study is to map the female reproductive tract microbiome in patients with and without endometriosis to seek correlations of the microbiome to endometriosis, to determine if lower reproductive tract microbiome is predictive of upper reproductive tract changes by comparing composition of the microbiome in the lower and upper reproductive tracts, to explore immunologic differences in patients with and without endometriosis, compare presence of immunologic factors and cells between ectopic and eutopic endometrium, and to compare systemic immune system characteristics in patients with and without endometriosis using mass cytometry of peripheral blood samples.

The purpose of this study is to evaluate the diagnosis of endometriosis by gross visualization and compare to histologic evaluation during laparoscopic resection. By better understanding the polymorphic appearance of endometriosis, it will improve our diagnostic potential without having to rely on pathology. With this knowledge, it will improve patient centered care and possibly expedite treatment.

The objective of this study is to conduct a prospective randomized controlled trial of robotic-assisted versus conventional laparoscopy for the treatment of endometriosis.

The purpose of this study is to demonstrate the feasibility of F18- FES PET/MRI in patients with endometriosis, to establish the normal bio-distribution of F18- FES in pre-menopausal women, and to compare the diagnostic performance of F18- FES PET/MRI with that of conventional imaging (ultrasound and MRI alone) using surgical findings as the reference standard.

The purpose of this study is to analytically validate a cluster of specific biomarkers for endometriosis diagnosis and disease recurrence. This signature will be tested on endometrium and blood from 975 patients, divided in two groups : 550 patients affected by endometriosis and 225 patients unaffected (controls). EndoSearch is not about drug or medical device assessment but a research study for biomarker analytical validation purpose.

The purpose of this study is to investigate if complete pelvic peritonectomy is associated with improved quality of life in patients with chronic pelvic pain without histologic diagnosis of endometriosis as compared to patients with histologic diagnosis of endometriosis. 

The purpose of this study is to investigate the value of ultrasound imaging of microscopic blood vessels as a new biomarker for identifying the difference between benign and cancerous uterine pathologies, and to compare ultrasound imaging to the diagnostics of MRI and (if available), surgical pathology.

The purpose of this study is to investigate the safety and effectiveness of FE 999049 compared to placebo in women aged 35-42 years old.

The purpose of this study is to investigate the safety and effectiveness of FE 999049 compared to placebo in women aged 18-34 years old.

The aim is the characterization of the microbiome of subjects experiencing benign reproductive tract disorders and its comparison to the microbiome present in individuals lacking that disorder.

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• Published: 04 December 2023

Time for global health policy and research leaders to prioritize endometriosis

• Linda C. Giudice   ORCID: orcid.org/0000-0002-1677-0822 1 ,
• Andrew W. Horne   ORCID: orcid.org/0000-0002-9656-493X 2 &
• Stacey A. Missmer   ORCID: orcid.org/0000-0003-3147-6768 3 , 4  

Nature Communications volume  14 , Article number:  8028 ( 2023 ) Cite this article

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• Public health
• Reproductive disorders

Endometriosis is an incurable, under-diagnosed, systemic inflammatory disease affecting millions world-wide. Common symptoms include life-impacting pain, gastrointestinal/urinary symptoms, excessive fatigue, and infertility. Global public health policies are urgently needed to promote awareness, implement multidisciplinary care, and fund research for aetiology, biomarker discovery, and effective therapies for symptoms associated with endometriosis.

Patient and public health impact of underinvestment in endometriosis

Defined by endometrium (uterine lining)-like tissue outside the uterus, endometriosis is a little known, common, hormone-dependent, inflammatory disorder currently diagnosed by surgical or radiologic visualisation of disease 1 . While mainly associated with life-impacting pelvic pain, painful menstruation and sexual intercourse, infertility, fatigue, and depression, those affected also have higher risk of non-reproductive sequelae, including high blood pressure, cardiovascular disease, autoimmune conditions, gastrointestinal and urologic symptoms, multifocal pain, migraines, and ovarian and breast cancer 1 (Fig.  1 ). Endometriosis affects ~10% of persons with a uterus, commonly striking teens and persisting across the reproductive life span (and sometimes beyond), greatly impacting personal relationships, educational and employment opportunities, and quality of life 2 , 3 . Risk of developing disease is ~50% genetic, with no specific “endometriosis gene” or consistently identified environmental triggers 1 .

Basic research is key to understanding its causes and molecular and genomic underpinnings, leading to novel diagnostics and therapeutics to alleviate symptoms and ultimately discover a cure. Education of professional and lay communities and leaders throughout the world about endometriosis and its intersection with social determinants of health are key components to improve the lives of those affected. Moreover, multidisciplinary care is essential for holistic management of this complex and multi-dimensional disorder.

Reliance on surgery and marginal advances in medical therapies for symptom relief maintain delayed diagnosis and insufficient care for many 1 . Moreover, menstrual stigma, pain in women, sexism, and racism are impediments globally for life-improving care 3 , 4 . Lack of awareness and/or discomfort regarding menstrual health remains surprisingly prevalent among healthcare providers 3 , 4 .

Clinical specialties are commonly siloed, which diminishes recognizing and addressing endometriosis in clinical practices and specialist care outside gynecology 1 , 3 . Siloed structures also negatively impact awareness and applying cutting-edge technologies to multidisciplinary scientific discovery of causes, diagnostics, and treatments for endometriosis 3 , 4 , 5 . Impediments to determining aetiology and pathophysiology, classifying clinically-relevant subphenotypes, diagnosing, and treating endometriosis include socio-cultural factors that continue its obscurity among practitioners and the public 1 , 3 , 4 . Here we summarize challenges in endometriosis care and advancing research in this space.

A primary hypothesis for pelvic endometriosis establishment is through transplantation of endometrial tissue refluxed through the oviducts during menses, attaching to and invading pelvic organs, and eliciting a profound inflammatory response and fibrosis 1 . This is replicated in experimental rodent models that utilize seeding with heterologous or homologous endometriotic tissue 7 . However, this paradigm is insufficient, as nearly all persons with uteri experience “retrograde menstruation” and rodents do not menstruate. Thus genetic, epigenetic, hormonal, immunologic factors, endometrial stem cells, and coelomic metaplasia, have been implicated in establishment/survival of lesions (with pathway-informative somatic mutations)—complementing the theory that retrograde menstruation plays a causal role 1 , 4 . While mechanisms underlying this complex pathophysiology are slowly being elucidated, a comprehensive understanding of disease origins is wanting. This has stalled comprehensive animal models with disease fidelity—hampering research on endometriosis overall 6 .

Mechanisms underlying endometriosis-associated pain are complex 7 . Key to establishing lesions and activating peripheral pain pathways are new blood vessels and nerve sprouting (neuroangiogenesis) 7 . Also, in the central nervous system, brain volume and regional biochemical alterations accompany chronic endometriosis-related pain 7 . Endometriosis is also associated with infertility—attributed to scarred Fallopian tubes, diminished egg quality, and/or disrupted hormone signaling within the uterus 1 , 3 , 4 . Improved understanding of endometriosis pathogenesis and its complex and heterogenous manifestations and physiologic impacts are essential to develop improved diagnostics and patient-centred therapies.

Heterogeneous presentation of endometriosis impedes diagnosis and treatment

Most pelvic endometriosis comprises three subtypes: superficial peritoneal, ovarian cysts (“endometrioma”), and deep disease 1 . Symptom manifestation and severity vary, and underdiagnosis is common due to erroneous symptom normalization and overlap with other diseases 8 . Recently, refined imaging techniques identify, with high accuracy, ovarian and deep disease, but reliance on surgical visualisation for the most common superficial peritoneal lesions continues to impede timely diagnosis 3 , 4 . Surgery or imaging requires access to healthcare services, which varies significantly across socio-economic and racial/ethnically underserved groups and geographies 4 , 9 . Average diagnostic delay is 7 years after symptom onset, with delays >10 years not uncommon 4 , 9 . There remains no reliable non-invasive biomarker of any endometriosis subtype 4 .

Treatment of pain symptoms falls broadly into surgical removal of disease and associated adhesions and hormonal suppressive therapies, including combined oral contraceptive steroids, progestins, gonadotropin releasing hormone analogues, androgens and aromatase inhibitors 10 . Medical therapies that decrease oestrogen (or counter oestrogen action) are prescribed, because steroids play a key role in the pathophysiology of endometriosis 1 . Unfortunately, both approaches are suboptimal. Surgery is associated with recurrence rates up to 50% within 5 years, and contraceptive hormone treatments often have unacceptable side effects and are counterproductive to fertility goals 10 . Geographic and financial barriers to accessing treatment from endometriosis-trained healthcare providers are common 9 . Surveys of patients consistently highlight symptom relief and improved medical therapies that do not limit fertility as a top priority for research 3 . Historically, pharmaceutical companies were reluctant to develop new drugs for endometriosis, and focus has been on variations of hormonal, anti-inflammatory, or repurposed therapies 11 , lacking revolutionary impact. While novel treatment discovery is essential, clinical trials for endometriosis have been plagued by widespread variations in outcome reporting, and only a fraction of completed trials is published 11 .

Emerging chronic pelvic pain-focused therapies that include considerations of neuropathic and nociceptive pathways have not been adequately studied 12 . Those with persistent/recurrent pain have a high rate of hysterectomy 12 which does not eliminate pain recurrence and may heighten risks for multiple conditions later in life 1 , 10 . Further, commonly reported life-impacting concerns including fatigue and impaired sexual functioning have yet to be targeted for treatment among patients with endometriosis. A critical impediment to discovery of novel diagnostics and treatments and personalized approaches is the lack of a prognostically correlated classification of the highly heterogenous presentation of endometriosis lesion types and symptoms, which includes variation and evolution within patients across the life-course 3 , 4 .

Endometriosis funding landscape and the socioeconomic cost of underinvestment

The first economic study (2011) revealed the average cost of endometriosis was ~€9579/woman/year (€6298 lost work-productivity, €3113 direct health care costs)—similar to diabetes, Crohn’s disease, and rheumatoid arthritis 13 . However, unlike these well-known diseases with similar socioeconomic impact and burden but considerably lower prevalence in the general population, there is relatively little investment in research into causes and disease mechanisms of endometriosis 5 . Recent governmental attention has included an increase in NIH funding for endometriosis research to $16 M (0.04% of the total NIH budget) for the year 2022 ($2/person with endometriosis/year), while Crohn’s disease received $90 M ($130/person with Crohn’s/year) 14 . Data consistently demonstrate that female-specific conditions are disproportionately underfunded 5 . Further, female reproductive conditions are largely absent from open access reference databases on which much of advanced biomolecular data science relies (e.g., ENCODE, NIH Roadmap epigenomics, GTEx, TissueNexus), impeding novel discovery, although recent endometrium and endometriosis single-cell transcriptomic data should soon appear in the Human Cell Atlas 4 .

Commitments to endometriosis research and care and moving forward

Despite identification of endometriosis as a chronic inflammatory pain condition with multi-systemic symptoms and co-morbidities 1 , 8 , as a disease associated with menstruation and pelvic pain, it is still generally considered a gynaecologic disorder. This reductive concept has resulted in lowered healthcare system and research prioritization, limited integration, and impeded translation of rapidly developing scientific, multi-omic, genetic, bioengineering, and clinical discoveries in pain and inflammation. Their application would hasten identifying shared and unique features of endometriosis, leading to novel therapeutics and multi-disciplinary approaches to symptom management.

Essential to improving diagnosis and care for endometriosis patients is ensuring they are heard and believed when expressing their symptoms to themselves, their personal support networks, and especially to healthcare providers 4 , 10 . The 2021 WHO Endometriosis Fact Sheet ( https://www.who.int/news-room/fact-sheets/detail/endometriosis ) is a welcome leap forward to increase awareness globally. We posit that education and improved awareness including menstrual wellbeing curricula within schools for students of all gender identities could overcome menstruation taboos, ensure understanding of a ‘normal’ period, and when to seek help for distressing symptoms. Improved medical education regarding menstruation and endometriosis signs and symptoms could be ensured with thoughtful targets, e.g., including questions about menstrual health and non-malignant gynaecologic conditions on medical training board examinations, and larger scale initiatives such as revision of didactic teaching and medical curricula to prioritize menstrual health as critical to patient care.

Once diagnosed, individuals with endometriosis require personalised, multimodal, interdisciplinary treatment across the life-course to meet challenges of the evolving disease and changing patient priorities. First proposed in 2006, this novel care approach is optimally delivered through specialist centres comprised of integrated services including gynaecologists, endometriosis specialist nurses, and experts in imaging, pain medicine, psychology, physiotherapy, fertility, colorectal surgery, urology, and gastroenterology 15 . Whilst specialist centres have been successfully implemented in the UK and a few European countries (e.g., Denmark, Germany, France), this is not standard of care worldwide. Importantly, care delivery models incorporating mobile and digital technologies, and including primary care providers, specialists, pharmacy-based, community-based, and risk-prevention approaches, offer great opportunities and need development and investment 4 . For example, the Australian National Action Plan for Endometriosis launched in 2018 with $58 M additional funding in 2022 supports a 4-year plan to fund research and establish specialist endometriosis and pelvic pain clinics in every state and territory. Restructuring similar models globally could fulfil personalized care in all regions.

As delayed or undiagnosed endometriosis leads to compromised health, promoting awareness, improving access to care, and implementing multidisciplinary care paradigms are urgently needed in global public health policies. Equally urgent and important are prioritizing and committing resources to support fundamental research and biomarker discovery to shorten the protracted time to diagnosis and provide effective, long-term therapies for this chronic and debilitating disorder to the benefit of millions world-wide.

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Acknowledgements

The authors thank Kevin Kuan, University of Edinburgh, for Fig.  1 graphic design and critical content editing.

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Distinguished Professor, Center for Reproductive Sciences, Center for Reproductive Health, Department of Obstetrics, Gynecology and Reproductive Sciences, University of California, San Francisco, San Francisco, CA, USA

Linda C. Giudice

Professor of Gynaecology and Reproductive Sciences, EXPPECT Edinburgh and Centre for Reproductive Health, University of Edinburgh, Edinburgh, UK

Andrew W. Horne

Professor of Obstetrics, Gynecology, and Reproductive Biology, Michigan State University, Grand Rapids, MI, USA

Stacey A. Missmer

Adjunct Professor of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

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Contributions

L.C.G. conceived the topic and wrote the initial draft, which was extensively revised with A.W.H. and S.A.M.. L.C.G. contributed much of the scientific information about endometriosis pathogenesis and pathophysiology. A.W.H. contributed key concepts about public health relevance and endometriosis clinical symptoms, clinical care, and health disparities. S.A.M. contributed key concepts in the epidemiology of endometriosis, status of funding for research and multidisciplinary care models. L.C.G., A.W.H., and S.A.M. each provided references throughout the manuscript and in areas of their expertise and assured accuracy of citations and worked as a team on revising the manuscript resulting in its final form.

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Correspondence to Linda C. Giudice .

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Competing interests.

L.C.G. is funded by the National Institutes of Health P01 HD106414, “UCSF Stanford Endometriosis Center for Discovery, Innovation, Training and Community Engagement”. She is co-author of patent filed by the Regents of the University of California, San Francisco, U.S. Application Serial No. 63/149,022, “Endometriosis-Related Methods and Compositions”. She is past-President of the World Endometriosis Society and the American Society for Reproductive Medicine, and is a consultant for Celmatix, Myovant Sciences, and Gesynta Pharma. AH’s institution (University of Edinburgh) has received payment for consultancy and grant funding from Roche Diagnostics to assist in the early development of a possible blood diagnostic biomarker for endometriosis. A.W.H.’s institution has received payment for consultancy fees from Gesynta and Joii. A.W.H. has received payment for a presentation from Theramex. A.W.H.’s instutution has received grant funding from the MRC, NIHR, CSO and Wellbeing of Women for endometriosis research. A.W.H. is listed as a co-inventor on a UK Patent Application (No· 2217921·2). A.W.H. is President-elect of the World Endometriosis Society and co-Editor in chief of Reproduction and Fertility. AH has been a member of the NICE and ESHRE Endometriosis Guideline Groups. AH is a Trustee and Medical Advisor to Endometriosis UK. S.A.M. receives research support from National Institutes of Health, USA Department of Defense, AbbVie, and Marriott Family Foundations. She is President of the World Endometriosis Society, the Field Chief Editor for Frontiers in Reproductive Health and has served on advisory boards for AbbVie, Roche, and Abbott.

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Giudice, L.C., Horne, A.W. & Missmer, S.A. Time for global health policy and research leaders to prioritize endometriosis. Nat Commun 14 , 8028 (2023). https://doi.org/10.1038/s41467-023-43913-9

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Spotlight: NIH Panel Explores Endometriosis Advances, Emphasizes Awareness

Around 200 million girls, women, and transgender men worldwide live with endometriosis, a disease in which tissue similar to the lining of the uterus grows in other places in the body. It is one of the most common gynecological diseases, with symptoms that include pelvic pain, fatigue, and infertility. Those who have the disease often endure a long, difficult path to diagnosis and effective treatment.

Panel participants include: 

• Diana W. Bianchi, M.D ., director, NICHD
• Janine Clayton, M.D., FARVO , director, NIH Office of Research on Women’s Health (ORWH)
• Moderator: Candace Tingen, Ph.D. , chief of the NICHD Gynecologic Health and Disease Branch

The Q&A has been edited for length and clarity.

All too often, women—and especially women of color—are dismissed when they talk to their doctors about their pain and symptoms that might relate to endometriosis. Why is it important to elevate awareness and education around this, particularly for women of color who are experiencing this disease?

That's why it is so critical that we raise awareness so we can interrupt that bias and be mindful that people express their pain differently. We need to make sure that our medical providers, our nurses, and other individuals in the health care system not only receive education about endometriosis but also about pain, because the pain is the signal that something isn't right.

As a physician I usually say: You are the world's expert on your own body. I need to believe what you tell me. I need to understand what you're telling me, and we need to figure out what we can do to make you feel better regardless of what we do or don't know about that disease.

The White House recently launched its Initiative on Women's Health Research. How might this initiative make an impact on research for endometriosis and other reproductive diseases that affect women?

Dr. Clayton: The White House Initiative on Women’s Health Research says that at the highest level we are recognizing that we have to address our gaps in knowledge of women's health and that we have to accelerate research on the unique and specific health needs of women, such as endometriosis, across their lifespans. This initiative involves multiple government agencies.

It’s a very clear, very focused mission to advance women's health research in the United States. Endometriosis is specifically mentioned in the presidential memo, and we’re happy to see [the inclusion of] gynecologic conditions like pain and other important female-specific issues that deserve attention. We would love to see this bring more scientists from different disciplines to the field, to bring their skills and expertise for innovation from industry.

Public-private partnerships are called out in this presidential memo to accelerate progress because we want to make sure that advances from publicly funded research translate into practical benefits for health care providers, so that they know how to better treat people to relieve their symptoms.

It’s critical that we ensure that we also strengthen the workforce for people who are studying women's health so that we can train future researchers and increase public awareness. Everyone needs to understand how important this is and to make sure that women's health outcomes are prioritized.

Is there a link between endometriosis lesion size, lesion presence, or lesion stage and pain? Pain is a primary symptom in this disease, but how does that pain connect to the manifestations of the disease?

One of the critical aspects that has been evolving is our understanding that what patients experience is very heterogeneous. While that is challenging, it is also a great gift. Both clinically and scientifically, we are leaning into those differences, being curious about the physiology that underlies them, but also focusing on what we need to discover to give clinicians the tools they need. So, when they first sit down with a patient, they know more about what characteristics of each patient they need to define and understand. That will help to precisely choose the best diagnostic and treatment pathways, leading us to better success with current treatments and to many possibilities for novel treatments.

Is there a link between endometriosis and autoimmune disorders?

Dr. Missmer: We know that there is an association between endometriosis and autoimmune conditions and that women with endometriosis have about double the risk for autoimmune conditions such as rheumatoid arthritis, lupus, and multiple sclerosis. We know that there is an immune dysregulation in those with endometriosis. This is leading to identification of  novel anti-inflammatory pathways and chronic inflammation pathways and immune dysregulation relationships with endometriosis. Hopefully, this knowledge will lead to new treatments, but also a better understanding of menstrual health, menstrual function, and gynecology in general.

The path to diagnosis for someone with endometriosis can be long and circuitous. Because symptoms can start early in a women's life, it seems like that's a good point for intervention. How is NICHD exploring pathways for non-invasive diagnosis and new treatments?

Through the SBIR program, we also are funding development of non-hormonal therapeutics. The idea is that this therapeutic would kill endometrial cells at the source and prevent them from growing. We're also making progress in new and improved treatments, both in mouse models and in human beings. We've taken advantage of a technique that's used in cancer in which hyper-magnetic fields are used to kill cells. The endometrial cells have the potential to have magnetic nanoparticles administered to them, and researchers then can use this hyper-magnetic field to destroy those cells. It's working well in mice, it's reducing the lesions, and also enabling subsequent pregnancy in mice.

We previously funded development of compound that significantly reduces pain called elagolix (Orlissa ® ) which is essentially a hormone blocker. It’s one of the only FDA-approved therapeutics for endometriosis pain. Another recently funded study has been looking at oleuropein , which is a compound that comes from olives that has the potential to treat endometrial cells.

Could you tell us about the new Office of Autoimmune Disease Research (OADR) within ORWH, its origins, and how endometriosis fits in?

Dr. Clayton: About 8% of people in the United States are living with an autoimmune disease, and nearly 80% of those people are women. So, the fact that women are so predominantly affected by autoimmune disease has made it important for many institutes and centers (ICs) at NIH. In 2022 Congress appropriated funds to form OADR within ORWH. Our inaugural director, Vicki Shanmugam, MBBS, MRCP, FACR, CCD, a renowned physician, scientist, and rheumatologist, will be helping us focus on a variety of autoimmune diseases.

Because we were able to support some endometriosis research last year through these funds, we are considering a wide range of autoimmune diseases or diseases with immune dysregulation as part of the remit of OADR. We will be working with all the ICs, as we do for almost everything we do, to drive some interdisciplinary approaches. We have so many questions, and we need to investigate many aspects. By bringing multiple disciplines together through interactive, interdisciplinary approaches, we hope that we'll be able to accelerate progress through OADR. We are looking forward to working further with all the ICs, in particular the National Institute of Arthritis Musculoskeletal and Skin Diseases and the National Institute of Allergy and Infectious Diseases.

Endometriosis can be such a spectrum of disorders. How is research on the disease’s presentation in different individuals getting us to diagnosis, intervention, and treatments earlier? What progress are we seeing?

Dr. Missmer: A huge credit goes to NICHD, which has funded my team and others to look at multisystemic and the broader consequences and associations with endometriosis. Learning more about the different systems and pathways that are involved for some patients with endometriosis encourages curiosity from many different disciplines to bring together those footprints.

We're leaping forward in our knowledge, and that knowledge is critical to defining different presentations of endometriosis in terms of the varied symptoms that patients experience. Also, we're now starting to delve more deeply into patterns around basic science and biomarker technology. Work from Naoko Sasamoto, M.D., and Kathryn Terry, Sc.D., is looking at proteomic profiles , and we're starting to see that the proteins in the blood are different between those patients with endometriosis who are presenting with dysmenorrhea, compared to those who are presenting with cyclic pain or those who have autoimmune conditions.

We're seeing differences in the tissue-based mutations between endometriosis lesions that are deep and those that are superficial. That means that the treatment pathways may be very different between a woman who presents with certain characteristics and not others. It also may mean that we can identify who among those with endometriosis is at risk of developing another immune condition. For example, who with endometriosis is at risk of developing hypertension and heart disease? We can then craft a better understanding of what's driving that relationship. We also have intentional interventions to prevent and improve long-term health starting early in life, and not at the point when a person is already experiencing infertility or autoimmune conditions.

How does endometriosis fit into the NICHD Strategic Plan and how does NICHD support research in this area?

Dr. Bianchi: Our institute was founded as a life-course institute, not disease-based. When we were creating our strategic plan in 2020, we talked a lot about how it would be important to focus on conditions that had major gaps in knowledge and needed more research.  We settled on endometriosis as one of our 10 aspirational goals in the strategic plan.

The goal was to do a better job of diagnosing, managing, and treating endometriosis because it affects 1 in 10 people who are born female. As we refresh our next strategic plan, I'm hoping that this increased focus on women's health research will align with some of the needs for endometriosis, but also with other painful diseases associated with gynecological health.

There are reasons to be optimistic. Between 2020 and 2022, the number of endometriosis projects that we funded has gone from 32 to 52 and the amount of total endometriosis funding at NIH has gone from $13 million to $27 million. What we've seen in other areas is when there's an infusion of funds it brings in new researchers from other disciplines, and it has an enormous impact on the field.

Sasamoto N et al ., Plasma proteomic profiles of pain subtypes in adolescents and young adults with endometriosis. Human Reproduction . DOI: 10.1093/humrep/dead099 (2023) 

• Open access
• Published: 22 March 2023

Shining a light on endometriosis: time to listen and take action

Bmc medicine.

BMC Medicine volume  21 , Article number:  107 ( 2023 ) Cite this article

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Endometriosis, an often severe and common chronic inflammatory condition, affects around 1 in 10 women of reproductive age worldwide. It can have devastating effects on women’s physical and emotional well-being, quality of life, and reproductive health. Across the globe, March has been declared Endometriosis Awareness Month for a reason—it is time to increase awareness and education to allow for early diagnosis and eliminate the stigma surrounding this often-misunderstood condition. This editorial will shed light on endometriosis and explore why it is important to start listening and take action.

Endometriosis is characterized by tissue that normally lines the inside of the uterus growing outside, usually in the pelvic area. During the menstrual cycle, this displaced tissue continues to thicken, break down, and bleed, just like the tissue inside the uterus, causing a chronic inflammatory reaction that may result in scar tissue formation. Oftentimes, the endometrial tissue grows on pelvic organs such as the ovaries, fallopian tubes, and the outside of the uterus, resulting in fibrotic lesions and adhesions. Notably, the extent of endometrial lesions does not necessarily correlate with the severity of symptoms. Patients can experience severe symptoms despite the absence of visibly large lesions and vice versa, and they can even be asymptomatic.

Patients with endometriosis often suffer from pain in diverse manifestations, such as chronic pelvic pain, painful periods, and pain during intercourse, ranging from mild discomfort to severe pain. Some patients may experience heavy or irregular menstrual bleeding and fatigue, possibly resulting from chronic pain and inflammation often associated with this condition. Even worse, endometriosis can compromise reproductive health and cause infertility, leading to problems in getting pregnant.

These symptoms vary broadly, and not all endometriosis patients may experience them with the same intensity. Some patients may not experience any symptoms at all, putting them even more at risk for a delayed diagnosis and treatment. Symptoms may also change over time and often, but not always, improve after menopause.

The symptomatic ambiguity and the lack of awareness of endometriosis among both patients and healthcare providers often lead to underdiagnosis and prevent timely treatment of this condition, which has significant social, public health, and economic implications. Severe pain, fatigue, and infertility can all contribute to a significantly impaired quality of life for those affected by endometriosis. In the worst cases, the debilitating pain prevents them from pursuing regular day-to-day activities and attending school or work. Moreover, their sexual health and partnerships might be affected by painful intercourse and infertility.

Consequently, those affected often develop mental health problems and may suffer from depression or anxiety, accompanied by feelings of frustration, loneliness, and even shame, leading to a downward spiral and complex multimorbidities. Too often, patients get relief from their symptoms only after spending years with unsuccessful consultations or continue to suffer in silence as they interpret their symptoms as a normal part of their menstruation, which their healthcare providers may echo. For example, in the UK, more than half of people do not know about endometriosis, including 62% of women between the age of 16 and 24. But why is there such low awareness despite the high prevalence and devastating consequences?

The underlying problems are diverse and spread across different levels. At the scientific level, we must acknowledge that endometriosis remains an underresearched condition. Research efforts towards a better understanding of the pathophysiology and diagnostic treatment options are progressing only slowly. At the societal level, the situation is worsened by the normalization of women’s pain and persisting stigmatization around menstrual issues, which becomes even more problematic when entering the clinical level: Many people, including healthcare providers, may dismiss the symptoms of endometriosis as “normal” menstrual pain, leading to a delay in diagnosis and treatment. Additionally, the stigma surrounding menstruation and reproductive health can add barriers to seeking help, making those affected endure the consequences silently.

Therefore, we urgently need approaches towards better disease management, education, and awareness involving all relevant stakeholders to eliminate stigmatization and provide timely diagnosis and treatment. It is important to note that there is no cure at the moment. Still, good management options, including pain management, hormone therapy, or surgery, can significantly improve patients’ lives. For example, studies suggest a 62.5% improvement or resolution of pain 6 months after laparoscopy, a standard surgical treatment to remove endometrial tissue, with 90% still improved 1 year post-surgery. However, the average time to diagnosis is lengthy, and it can take over 7 years for patients to receive a proper diagnosis and, thus, treatment.

Simple solutions seldom resolve complex problems. Improving the lives of patients with endometriosis will require a multifaceted approach that involves the scientific community, healthcare providers, and society at large by focusing on the following:

Research funding : We must invest in endometriosis research to build knowledge about the pathophysiology and develop new treatments. Advocacy groups and government agencies should be encouraged to fund studies to increase our understanding of the condition and provide better treatment options.

Medical education : Medical schools and residency programs should include more information about endometriosis and its symptoms to ensure that healthcare providers can recognize the condition earlier and provide timely and appropriate care.

Patient advocacy and public awareness campaigns : Support groups for people with endometriosis should be encouraged to share information and resources on various platforms, such as social media and blogs. Providing an open forum for exchange will help increase the chances of early diagnosis and alleviate patients’ mental burden by making them feel heard and connected.

Working collaboratively, patients, advocates, healthcare providers, and researchers can significantly improve care for those affected by endometriosis and break new ground. The Endometriosis Awareness Promotion Project ( EAPP ), a multinational and multicentre epidemiological study, is an excellent example of how collaborative efforts can lead to meaningful action: This study explores the key aspects of menstrual pain and endometriosis, including its personal and social impact. Promising first results suggest that an educational scheme can improve young women’s awareness and knowledge of endometriosis, highlighting the role of education for better outcomes.

Although initiatives such as the EAPP are encouraging, women’s health has been neglected for far too long. To shake things up and eventually improve the lives of those impacted by endometriosis, we must continue raising awareness at all levels. These efforts will pave the way for achieving the core goals proclaimed by the UK Endometriosis Association: reducing diagnosis time and providing access to treatment and support for patients. By taking action against endometriosis, we can make a huge difference in the lives of those affected and empower them by supporting their human right to the highest standard of sexual and reproductive health.

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BMC Medicine. Shining a light on endometriosis: time to listen and take action. BMC Med 21 , 107 (2023). https://doi.org/10.1186/s12916-023-02820-y

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Understanding Endometriosis: From Symptoms to Treatment

Knowledge and News on Women’s Health (KNOWH) blog from FDA Office of Women’s Health

March is Endometriosis Awareness Month and is an opportunity for all women to understand more about this condition, what symptoms to look for, and potential treatment options they can discuss with their health care providers.

What is endometriosis? 

Endometriosis (en-doe-me-tree-O-sis) is a condition where tissue similar to the lining of the uterus grows in other places in the body. It is one of the most common gynecological diseases, and its primary symptoms include pain and infertility. 1  Endometriosis may affect more than 11% of American women between 15 and 44. Endometriosis can develop in any girl or woman who has menstrual periods but is especially common among women in their 30s and 40s and may make it harder to get pregnant. 2

Endometriosis growths are benign (not cancerous). But they can still cause problems. Endometriosis growths may swell and bleed in the same way the lining inside of your uterus does every month—during your menstrual period. This can cause swelling and pain because the tissue grows and bleeds in an area where it cannot easily get out of your body. 2

Women with endometriosis may experience a variety of symptoms which may include:

• Heavy menstrual periods 
• Problems getting pregnant
• Painful menstrual cramps that may worsen over time
• Painful bowel movements or pain when urinating during menstrual periods
• Pain during or after sex
• Pain in the intestine or lower abdomen
• Bleeding or spotting between menstrual periods
• Stomach (digestive) problems such as diarrhea, constipation, bloating, or nausea, especially during menstrual periods

If you are experiencing any of these symptoms talk with your health care provider. They may perform a pelvic exam, an imaging test (such as an ultrasound), or a laparoscopy, a type of surgery that doctors can use to look inside your pelvic area, to determine if you have endometriosis.

Treatment for endometriosis

There is no cure for endometriosis, but treatments are available for the symptoms and problems it causes. In 2018, the U.S. Food and Drug Administration (FDA) approved elagolix (Orilissa®)  for the treatment of pain associated with endometriosis—the first and only pill specifically approved for endometriosis pain-relief. 3, 4  

Talk with your health care provider about which treatment options are best for you.

Learn more about endometriosis diagnosis and treatment at the following resources.

• Endometriosis - NIH National Institute of Child and Human Development (NICHD) 
• Endometriosis - HHS Office of Women’s Health 
• Endometriosis - NIH National Library of Medicine MedlinePlus

For resources and materials on other women’s health topics, visit www.fda.gov/womenshealthtopics .

1 https://www.nichd.nih.gov/health/topics/endometriosis 2 https://www.womenshealth.gov/a-z-topics/endometriosis 3 https://go.usa.gov/xzTRY 4 https://www.fda.gov/drugs/drug-approvals-and-databases/drug-trials-snapshots-orilissa

Imaging of Endometriosis: The Role of Ultrasound and Magnetic Resonance

• GLOBAL RADIOLOGY (J FRENCHNER, SECTION EDITOR)
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• Published: 18 February 2022
• Volume 10 , pages 21–39, ( 2022 )

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• Valentina Testini 1 , 2 ,
• Laura Eusebi 3 ,
• Gianluca Grechi 4 ,
• Francesco Bartelli 3 &
• Giuseppe Guglielmi   ORCID: orcid.org/0000-0002-4325-8330 1 , 2 , 5  

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Endometriosis is a chronic gynecological disease characterized by the growth of functional ectopic endometrial glands and stroma outside the uterus. It causes pelvic pain, dysmenorrhea, dyspareunia, or infertility. Diagnosis requires a combination of clinical history, non-invasive and invasive techniques. The aim of the present review was to evaluate the contribution of imaging techniques, mainly transvaginal sonography and magnetic resonance imaging to diagnose different locations and for the most appropriate treatment planning. Endometriosis requires a multidisciplinary teamwork to manage these patients clinically and surgically.

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Introduction

Endometriosis is a common gynecological inflammatory condition that is defined as functional ectopic endometrial glands and stroma outside the uterus. This disease affects women of reproductive age, with a prevalence of approximately 10% [ 1 ]. Patients can be asymptomatic or present with chronic pelvic pain and/or infertility.

The phenotypes of endometriotic lesions can be divided into three groups: pelvic endometriosis, ovarian endometriomas (OMA) and deep infiltrating endometriosis (DIE) [ 2 ]. In particular, pelvic endometriosis is defined as the presence of any endometrial tissue within the pelvic cavity, including the peritoneum, within any of the pelvic organs and inside the pouch of Douglas (POD). Ovarian endometriosis, an endometrioma, is defined as an ovarian cyst, of different size, lined by endometrial tissue. DIE is defined as endometriotic tissue that penetrates the retroperitoneal space for a distance of 5 mm or more and may be present in multiple locations, involving anterior or posterior pelvic compartments, or both [ 3 ]. Posterior DIE, a multifocal disease that may affect a variety of anatomical sites, represents the most common type of DIE [ 4 ]. The most typical sites of DIE include uterosacral ligaments (USL), rectovaginal septum (RVS), vaginal wall, POD and bowel, predominantly below the rectosigmoid junction. Anterior DIE corresponds to disease involving the anterior pouch or bladder and is much less common. DIE is a source of pain and infertility [ 5 ].

A frequently association with endometriosis is represented by adenomyosis, a disease characterized by infiltration of endometrial tissue into the myometrium [ 6 ].

Etiopathogenesis

Although the pathogenesis of endometriosis has not been fully elucidated, it is commonly thought that endometriosis occurs when endometrial tissue contained within menstrual fluid flows retrogradely through the fallopian tubes and implants at an ectopic site within the pelvic cavity [ 7 ]. In this process, menses transports viable endometrial fragments through the fallopian tubes to the peritoneal cavity, where they are able to implant, develop and sometimes invade other tissues of the pelvis [ 8 ]. In favor of this hypothesis is that all known factors that increase menstrual flow are also risk factors for endometriosis, including early age at menarche, heavy and long periods as well as short menstrual cycles [ 9 ]. The anatomical distribution of endometriotic lesions can also be explained by the hypothesis of retrograde menstruation as endometriotic lesions tend to have an asymmetrical distribution, which could be explained by the effect of gravity on menstrual flow, the abdominopelvic anatomy and the peritoneal clockwise flow of menses [ 10 ]. However, this theory does not explain the fact that although retrograde menstruation is seen in up to 90% of women, only 10% of women develop endometriosis [ 3 ]. Moreover retrograde menstruation does not explain the mechanism of endometrial tissue grafting onto the peritoneum. It is therefore evident that a variety of environmental, immunological and hormonal factors contribute to the onset of endometriosis, with mechanisms not yet known [ 11 ].

Genetic factors play an important role in the genesis of endometriosis, with an up to six times greater risk of developing the disease for first degree relatives of patients with endometriosis [ 12 ]. Despite this clear inheritance, the identification of the genetic factors that drive the disease is still incomplete.

The first step in diagnosing DE is to establish the patient's clinical history with particular emphasis on symptoms (dysmenorrhea, dyspareunia, dysuria, dyschezia, and chronic pelvic pain) as well as, age, height, weight, ethnic origin, gravidity, parity, previous surgery for endometriosis, family history of endometriosis, previous non-surgical treatment for endometriosis, and infertility. No symptom is specific to endometriosis [ 13 ].

However, several authors have underlined the poor relationship between symptoms exhibited by patients and the severity of the lesions rendering clinical diagnosis difficult. Moreover, it is thought that up to 50% of women could have asymptomatic endometriosis [ 14 , 15 ].

The second step is based on physical examination including a systematic analysis of the posterior vaginal fornix with a speculum to look for retraction and dark nodules. Digital examinations should be performed of the vagina to assess the characteristics of the uterus and adnexa, of the vesicouterine pouch to detect bladder invasion, and of the retrocervical area to detect infiltration of the torus uterinus, uterosacral ligaments (USLs), pouch of Douglas (POD), vagina, and rectovaginal septum (RVS) [ 13 ]. Rectal digital examination can help in assessing the involvement of the rectum, parametrium and visceral pelvic fascia. In the particular setting of DE, few data are available to evaluate the accuracy of physical examination. One retrospective study found that routine clinical examination detected DE in only 36% of 140 women with DE, and the authors suggest the accuracy of physical examination improves during menstruation [ 16 ]. To detect rectosigmoid and retrocervical DE without differentiating between the different specific DE locations, Abrao et al. reported that digital vaginal examination had a sensitivity of 72% and 68%, a specificity of 54% and 46%, respectively [ 17 ].

Laboratory tests are limited in the diagnosis of endometriosis (CA-125 has a detection rate of only 54% in patients with severe endometriosis 5 and is neither sensitive nor specific for the diagnosis) [ 18 ].

The gold standard for diagnosis of endometriosis is based on laparoscopy or surgery with histological verification of endometrial glands and/or stroma.

Imaging is needed to diagnose endometriosis and to plan treatment. The techniques used are transvaginal ultrasound (TVUS) and magnetic resonance imaging (MRI), the latter should be considered as a second-line technique after ultrasound [ 1 ].

Treatment of endometriosis is complicated and involves conservative approaches combined with medical therapies or surgery. Imaging is crucial to guide the type of treatment. The American Society for Reproductive Medicine Practice Committee states that “endometriosis should be viewed as a chronic disease that requires a lifelong management plan with the goal of maximizing the use of medical treatment and avoiding repeat surgical procedures” [ 18 ]. Current treatment is essentially surgical, medical, or a combination of both approaches. To this end, many patients are stratified for medical treatment with or without surgical treatment based on symptom severity or imaging results and desire to have children, with medical therapy typically including non-steroidal anti-inflammatory drugs, oral contraceptives, androgens, progestogens and gonadotropin-releasing hormone (GnRH) and/or surgery [ 19 ].

Laparoscopy is an effective surgical approach with the goal of excision of visible endometriosis in a hemostatic fashion. Radical surgery is reserved for those patients with severe symptoms where there is no desired fertility potential and especially when other forms of treatment have failed. Total abdominal hysterectomy and bilateral salpingo-oophorectomy are performed along with resection of any endometriotic lesions as completely as possible [ 4 ].

Transvaginal ultrasound (TVUS) is typically the initial imaging evaluation performed in patients with pelvic pain and infertility or when there is clinical suspicion for endometriosis. This examination is widely available with low relative cost and the sensitivity and specificity for detection of ovarian endometriomas and lesions in the rectal wall are high [ 18 ].

All patients should be examined systematically and carefully using an endocavitary sonography, with a microconvex array probe inserted transvaginally or transrectally. Both techniques are optimal approaches for examining uterus (including the different uterine zones: cervix, endometrium, junctional zone, and myometrium), adnexa, paracolpium, parametrium, vesicocervical, vesicovaginal, and rectovaginal spaces as well as urinary bladder, ureters, and rectum [ 20 ].

Limitations of sonographic technique include anterior compartment detection of endometriosis (bladder and vesicouterine pouch detection) and detection within the middle compartment (torus uterinus and round ligaments) [ 18 ].

The pelvic localization of endometriosis can be described according to three compartments (central, anterior, and posterior) according to functional and clinical relevance [ 21 ]. The anterior compartment includes the insertion site of the ureters, the bladder, the vesicouterine pouch, and the vesicovaginal pouch. The middle compartment contains the uterine body, fallopian tube, and uterine ligaments. The posterior compartment contains the uterosacral ligaments, rectovaginal septum, anterior rectal wall, and sigmoid colon [ 21 ].

Recently, the IDEA (International Deep Endometriosis Analysis group) published a consensus report 18 on the appropriate terms, definitions, and measurements that may be used to describe the sonographic features of the different phenotypes of endometriosis. A standardized pelvic TVS approach is proposed by this IDEA report consisting in four step pelvic evaluation [ 22 ]:

Evaluation of uterus and ovaries:

Evaluation of uterus: 2D–3D sonographic signs of adenomyosis

Evaluation of the adnexa: presence or absence of endometrioma or tubal pathology

Evaluation of TVS organ mobility (adhesions): adnexa and uterine mobility site-specific tenderness

Pouch of Douglas (POD) assessment using real-time ultrasound-based “sliding sign”

Assessment for DIE nodules in anterior lateral and posterior compartments

Anterior Compartment

The anterior compartment is comprised of the urinary bladder, the vesicouterine pouch, round ligaments and ureters. Involvement of the urinary tract occurs in approximately 1–2% of patients with endometriosis and involves bladder in 85% of these cases [ 23 ]. Ureteric involvement is found in 4% of patients with rectovaginal endometriosis [ 24 ]. The prevalence of round ligament endometriosis is estimated between 4.3% and 13.8% [ 25 ].

Bladder endometriosis is considered only in case of infiltration of the bladder wall and not in case of adhesions or superficial peritoneal implants on the bladder serosa.

Before TVS scan, patients are asked not to empty completely the bladder, because the slightly filled bladder permits to better evaluate the structure of the walls.

On ultrasound, bladder endometriosis appears as hypoechoic lesion, either containing cystic lesions or not, with regular/irregular margins of the bladder wall, bulging toward the lumen, involving the serosa, muscularis (most common), or (sub)mucosa of the bladder [ 26 ].

In the assessment of the bladder DIE localization, the bladder wall can be divided into three zones: the trigonal zone and vesical base; the vesical dome (which lies superior to the trigone and is intra-abdominal) and the anterior retroperitoneal bladder. Most frequently bladder endometriosis is located in the vesical dome on the posterior bladder wall close to the vesicouterine pouch [ 27 ].

Bladder adhesions of the vesicouterine pouch are evaluated by the presence or absence of the “sliding sign” between the uterus and the bladder [ 28 ].

During examination, from a longitudinal section through the cervix and moving the probe toward the lateral pelvic wall, it is possible to assess the distal part of the ureter adjacent to the bladder trigone, in order to evaluate the presence of stenosis and subsequent cephalad dilatation of the pelvic ureters. This finding can suggest direct invasion or compression of the ureter by endometriotic nodules, ovarian endometriomas, or adhesions [ 28 ].

The prevalence of ureteral endometriosis ranges from 0.01 to 1% of all patients with the disease and most often affect the distal segment of the ureter [ 29 ]. There are two types of endometriosis involvement of ureters: (1) extrinsic that represents 75–80% of the cases and is defined as the presence of endometrial tissue in the outer adventitia of the ureter that occurs as a nodule encasing the ureter by extension from pelvic foci; (2) intrinsic that represents 20–25% of cases and is defined as the presence of endometrial tissue in the mucosal and/or muscular layer of the ureter. Imaging signs are nodule or mass occurring in the ureter along its course, dilatation of the pelvic ureteral tract, or ureteropelvic hydronephrosis superior to the suspected lesion [ 22 ]. Pelvic ureteral dilation can be easily seen by TVS as a tubular anechoic image, very similar to a blood vessel but with negative color/power Doppler signs. An extrinsic compression, also without ureteral dilatation, is suspected in cases where a DIE lesion is located close to the ureter. The observation of a possible ureteral involvement requires transabdominal ultrasound to evaluate the renal pelvis. In all women with DIE, a transabdominal scan of the kidney to search for ureteral stenosis is necessary because the prevalence of endometriotic lesions in the urinary tract may be underestimated and women with DIE involving the ureter may be asymptomatic [ 30 ].

A review of the literature for bladder endometriosis reveals a reported mean US sensitivity of 55% and specificity of 93.5% [ 31 ].

For vesicouterine pouch endometriosis, two series reported US sensitivities and specificities of 16.7% and 33% and 99% and 100% [ 32 ]. These discrepant results could be partly explained by selection bias of inclusion among studies.

Central Compartment

The central compartment includes uterus and adnexa.

Adenomyosis is characterized by the migration and proliferation of endometrial glands and stroma from the basal layer of endometrium into the myometrium. It is associated with smooth muscle hyperplasia leading to an ultrasound image of ill-defined lesions within the myometrium [ 22 ].

Recently, the ultrasound features have been systematically described by the international Morphological Uterus Sonographic Assessment (MUSA) group [ 33 ].

According to the MUSA consensus, adenomyosis should be described as localized and diffuse.

Adenomyosis is classified as diffuse, if the total involvement of myometrium exceeds 50% of the corpus uteri (when the findings are present in only one part of the myometrium on one or more sites within the uterine wall), and localized (or focal) when less than 50% of myometrium is involved (one or more lesions) [ 33 ]. An adenomyoma is defined as a focal consolidation of endometrial glands and or endometrial stroma located within the myometrium with additional compensatory hypertrophy of the surrounding myometrium [ 27 ]. In rare cases it may present as a large cyst (adenomyotic cyst or cystic adenomyoma, with largest diameter 2 mm and echogenic rim) [ 34 ].

To evaluate adenomyosis, the size of the lesions should be measured (in particular the largest diameter of each focal lesion or the myometrial wall thickness in cases of a diffuse lesion), the involvement of the uterine layers and of the extent of the disease, based on the estimated volume of the uterine corpus affected by adenomyosis (mild < 25%, moderate 25–50%, and severe > 50%) [ 27 , 35 ].

According to several studies, there are different features associated with adenomyosis visible on 2D transvaginal sonographic [ 33 ].

On ultrasound, an adenomyotic uterus appears with a globular shape, enlarged dimensions, and uterine wall asymmetry. The myometrium typically appears inhomogeneous on gray-scale, characterized by the presence of an indistinctly defined area with either decreased or increased echogenicity with myometrial hypoechoic linear striations [ 36 ]. Round anechoic areas of 1-mm to 7-mm diameter, named myometrial cysts, also could be present within the myometrium [ 36 ]. In cases of focal adenomyosis, the adenomyotic lesion appears as a heterogeneous and hypoechogenic area within the myometrium, usually with anechoic lacunae or cysts with ill-defined contours and fan-shaped shadowing. These hypoechogenic areas reflect muscular hypertrophy of the myometrial tissue [ 27 ]. Irregularities of the endometrial-myometrial junctional zone is another common ultrasound marker in the diagnosis of adenomyosis [ 27 ]. This endomyometrial interface is normally visualized as hypoechoic tissue layer seen beyond the endometrial basal layer. In women with adenomyosis, the diffuse or focal hyperplasia and hypertrophy of myocytes determine whether diffuse or focal thickening of this zone is seen [ 37 ].

A characteristic sign is the “question mark sign” defined when the corpus uterus was flexed backward, the fundus of uteri was facing the posterior pelvic compartment, and the cervix was directed frontally toward the urinary bladder [ 38 ]. Investigators found 93% specificity and 75% sensitivity of this sign in detecting adenomyosis [ 22 ].

Power Doppler can be used to distinguish myometrial cysts from blood vessels and discriminate between leiomyomas and focal adenomyosis. Uterine leiomyomas manifest a circular flow along the myoma pseudocapsule, while localized adenomyosis and adenomyomas are characterized by diffusely spread vessels inside the lesions [ 39 ]. 2D ultrasound can yield equivocal result in the case of focal adenomyosis especially if there are coexistent fibroids. A meta-analysis of 14 trials and 1985 participants reported the sensitivity and specificity of ultrasound in the diagnosis of adenomyosis to be as high as 82.5 and 84.6%, respectively, values in line with MRI values [ 40 ].

The use of 3D vaginal ultrasound for the diagnosis of adenomyotic pathology allows a more complete evaluation in the sagittal, transverse and coronal planes, evaluating the ultrasound signs on the acquired 3D volume of the uterus [ 41 ].

Ovarian endometriomas occur when ectopic endometrial tissue in the ovary hemorrhages, forms a hematoma, enveloped by ovarian parenchyma (Fig.  1 ).

Endometriotic cyst, with regular parenchyma at the periphery, called “crescent sign” characteristic of benign lesions. Absent intralesional vascularization

An ovarian endometrioma has different imaging appearances on US, with the classic appearance being a cyst unilocular or multilocular (less than five locules) with homogeneous low-level echogenicity (ground glass echogenicity) of the cyst fluid, with increased posterior through transmission and no vascularization on color Doppler [ 22 ] (Fig.  2 ).

Color Doppler of multiple endometriomas of both ovaries, which appear enlarged and sharpened (ovarian kissing)

Another feature is the presence of peripheral echogenic foci (thought to reflect cholesterol deposits) seen in up to 36% of endometriomas. Endometriomas tend to be multilocular and bilateral (up to 50%) [ 42 ] (Fig.  3 ).

Endometrioma with evidence of the characteristic double fluid–fluid level. Inside the formation, hyperechoic spots can be highlighted, a symptom of hemosiderin accumulation

However, endometriomas may have a variable appearance because of the range of appearance of the internal blood products within them, which can cause fluid–fluid levels, echogenic regions, and papillary projections. In these cases, additional evaluation with MR imaging may be warranted to better evaluate and to exclude malignancy [ 43 ]. There is evidence that ovarian endometriomas originate from ovulatory events and it is likely that the number of endometriomas may increase with age, and multiple endometriomas in the same ovary may assume a multilocular morphology [ 44 ]. Guerriero and colleagues reported that ultrasound appearance of endometriomas differed between premenopausal and postmenopausal patients [ 44 ]. The endometriomas in the postmenopausal patients were less often unilocular cysts and less likely to exhibit ground glass echogenicity [ 27 ].

The primary differential diagnosis of an endometrioma is a hemorrhagic cyst. On US, a hemorrhagic cyst classically has internal reticular strands with retractile clot [ 18 ]. However, these features may not be seen, and instead, homogeneous low-level echoes mimicking that of an endometrioma may be present. Hemorrhagic cysts are unlikely to have the peripheral echogenic foci occasionally seen in endometriomas, and they are less likely to be bilateral or multifocal. Sonographic follow-up demonstrating resolution at 6–12 weeks is diagnostic of a hemorrhagic cyst [ 18 ].

Another differential diagnosis of an endometrioma is an ovarian epithelial neoplasm, which may contain low-level internal homogeneous echoes similar to an endometrioma. This imaging appearance was seen in up to 6% of ovarian serous cystadenomas in the study by Patel et al. [ 42 ] and in up to 20% of mucinous cystadenomas in the study by Van Holsbeke [ 45 ]. To better evaluate for the presence of malignancy (cystadenocarcinomas) in these cases, careful interrogation of the cyst should be performed to assess for internal solid components, such as papillary projections, mural nodules, and thickened septations.

Doppler helps avoid classifying malignancies as endometriomas, especially when evaluating a papillary projection. Generally, these different ultrasound criteria proposed have a sensitivity ranging from 62 to 73%, a specificity of 94–98% [ 46 ].

Masses in postmenopausal women whose cystic contents have a ground glass appearance have a high risk of malignancy. Borderline tumors and carcinomas arising from endometrioid cysts show a vascularized solid component on ultrasound examination [ 47 ].

The uterine tubes can be involved with endometriosis either with adhesions occluding the tube up to 6%) or by DIE foci affecting the tubal walls (up to 26% of the time) [ 18 ].

In case of endometriosis of the tube, we can observe a dilated tube with thick walls and incomplete septa with a fluid dense content similar to an endometrioma (hematosalpinx) [ 48 ]. A “cog-wheel” appearance of the longitudinal folds can be seen when the tube is imaged in cross-section. The presence of a hematosalpinx may be the only sign on imaging of endometriosis in the pelvis [ 49 ].

In case of occlusion of the tube due to adhesion or DIE that involved the distal part and the fimbriae, a hydrosalpinx is seen with the typical “beads-on-a-string” sign, defined as hyperechoic mural nodules measuring approximately 2–3 mm as seen on the cross-section of the fluid-filled distended structure [ 48 ].

The differential diagnosis of a hematosalpinx includes pelvic inflammatory disease (PID) or fallopian tube malignancies. Pyosalpinx of PID can be differentiated clinically by the presence of extreme tenderness on examination as well as the clinical signs of infection (fever, white count). On imaging, hyperemia surrounding the fallopian tube with fatty proliferation/edema in the adjacent fat suggests a pyosalpinx. Fallopian tube carcinoma presents sonographically with solid, vascular internal nodules within the fallopian tube and tends to occur in an older demographic group [ 43 ].

Posterior Compartment

Recently, the ultrasound features of the deep infiltrating endometriosis nodules have been systematically defined by the International Deep Endometriosis Analysis group [ 34 ]. The most common sites of the posterior compartment are posterior vaginal fornix/rectovaginal septum, uterosacral ligaments, anterior rectum/anterior rectosigmoid junction, and sigmoid colon [ 10 ] (Fig.  4 ).

Hypoechoic nodule of the rectosigmoid portion that obliterates the Douglas. At this level, the “sliding sign” can be seen, the sign of the sliding structures on each other which does not occur in the case of endometriosis

Deep endometriosis on sonography is subtle and presents as hypoechoic nodular or infiltrating regions. Occasionally, the infiltrative regions of DIE may have internal hyperechoic foci or complex internal cysts [ 50 ]. The differential diagnosis for DIE includes peritoneal implants; in these cases, to help differential diagnosis, an additional evaluation with MR is recommended [ 18 ]. Three-dimensional (3D) TVS has been also proposed in the evaluation of posterior locations of DIE without intestinal involvement, improving the diagnostic accuracy of 2D ultrasonography [ 51 ].

In the cases of DIE, it is necessary to describe of the anatomical localizations, the size and number of DIE nodules, the depth of infiltration of the nodules, and the degree of stenosis of the bowel lumen which is important to plan the surgical procedures [ 22 ].

Uterosacral Ligaments

The uterosacral ligaments (USL) are usually not visible on ultrasound. The uterosacral ligaments affected by deep infiltrating endometriosis can be seen in the longitudinal view of the uterus at the insertion on the posterior lateral cervix wall, as hypoechoic tissue, with regular/irregular margins within the peritoneal fat surrounding the uterosacral ligaments [ 13 ]. On the transverse cervical section, these hypoechoic nodules appear on the posterior lateral part of the cervix and interrupt the hyperechoic external cervical fascia. Sometimes, the uterosacral ligaments appear thickened and hyperechoic, probably as the morphologic expression of fibrosis, due to the chronic process of inflammation [ 27 ].

USLs lesions may be isolated or may be part of a larger nodule extending into the vagina or into other surrounding structures. In some cases, the DIE lesion involving the USL is located at the torus uterinus as a central thickening of the retrocervical area between USLs [ 52 ]. Two recent meta-analyses of USL endometriosis have reported pooled sensitivities and specificities of 53–64% and 93–97%, respectively [ 53 ].

In case of endometriotic lesions involving the uterosacral ligaments, special attention must be paid to the parametrium. Parametria are examined lateral to the uterine cervix first on the sagittal planes moving the probe from the lateral sites where the parametrium is attached to the cervix, to the uterine vessels bifurcation, to the lateral pelvic wall, and then on the transverse planes moving the probe from the uterine isthmus to the external cervical os. The parametrial involvement is seen as an infiltrating hypoechogenic irregular tissue, and it can be medially delimitated from the cervical vascular plexuses using color or power Doppler [ 22 ].

Rectovaginal Septum

Involvement of the rectovaginal septum should be suspected when an endometriotic nodule, which appears as hypoechoic solid nodule with smooth or irregular contours, that replaces the normal hyperechoic aspect of this layer between the vagina and the rectum, seen in the rectovaginal space below the horizontal plane passing through the lower border of the posterior lip of the cervix (under the peritoneum) [ 34 ].

Isolated rectovaginal septum nodule is rare, and it is usually an extension of posterior vaginal wall, anterior rectal wall, or both posterior vaginal wall and anterior rectal wall involvement. Hourglass-shaped or diabolo-like nodules can occur when endometriosis lesions from the posterior vaginal fornix extend to the anterior rectal wall [ 54 ].

DIE of the RVS may extend into the rectum and/or in the posterior vaginal fornix [ 22 ].

Major discrepancies exist between the pooled sensitivities and specificities provided by meta-analyses reporting values from 49% to 88% and 98% to 100%, respectively [ 34 ].

Vaginal endometriosis is diagnosed when the posterior or a lateral vaginal fornix shows a nodular wall thickened (> 5 mm) (mean normal vaginal thickness ranges from 3 to 5 mm), with or without round cystic anechoic areas, that does not get thinner with probe compression [ 13 ].

The nodule may be hypoechoic, homogeneous, or inhomogeneous with or without cystic areas and there may also be some vascularization at power Doppler. More frequently, the lesions are localized in the posterior vaginal fornix [ 22 ].

The insertion of saline solution in the vagina (sonovaginography) could improve the visualization of these lesions [ 55 ].

In a meta-analysis including ten studies, the pooled sensitivity and specificity of TVS was 57% and 99%, respectively [ 56 ]. Among the various TVS techniques, SVG provided the highest sensitivity and specificity reaching 91% and 89%, respectively [ 56 ].

The endometriosis affecting the bowel can appear as a thickening of the muscularis propria or as a hypoechoic nodule penetrating the intestinal wall with blurred margins, with or without hypoechoic or hyperechoic foci, usually associated with retraction and adhesion (the so-called Indian headdress sign), and few vessels at power Doppler evaluation [ 57 ].

The rectum and the rectosigmoid segment is the most frequent site of bowel involvement accounting for 70–88% of cases of bowel involvement with endometriosis, followed by the sigmoid colon, rectum, ileum, appendix, and cecum [ 10 ]. Intestinal nodules located below the peritoneum of the POD (or the level of the insertion of the USLs on the cervix in case the cul-de-sac is obliterated) are considered low rectal lesions, while the ones above this level are considered upper rectal or the rectosigmoid junction lesions. This virtual line should delineate the plane under the peritoneum of the POD and correspond laterally to the parametria and medially to the RVS. The lowest limit of the nodule on the bowel wall should be determined, because the lower rectal lesions are more difficult to remove surgically by shaving or segmental resection and have higher complication rate [ 22 ].

Endometriotic nodules of the rectum can be evaluated if necessary also by transrectal examination as well with the same transvaginal convex probe. This has the advantage of visualizing better the vagina, the rectovaginal septum (RVS), and the low rectal walls. Moreover, during the transrectal or transvaginal examination, a fluid contrast medium can be inserted in the vagina to visualize better the RVS (sonovaginography) [ 55 ]. It has been reported that adding water contrast in the rectum during transvaginal ultrasonography (RWC-TVS) improves the diagnosis of rectal infiltration in women with rectovaginal endometriosis. RWC-TVS is performed by injecting saline solution into the rectal lumen under ultrasonographic control through a catheter [ 58 ].

During the evaluation of posterior compartment, a negative “sliding sign” between the rectosigmoid and uterus could indicate an obliteration of the pouch of Douglas (POD), frequently associated with severe DE. Using this new technique, Reid et al. found sensitivity, specificity of 83.3%, 97.1% [ 59 ].

Multifocal lesions are defined as the presence of deep lesions within 2-cm area of the main lesions or multiple endometriotic lesions affecting the same intestinal segment. Multicentric lesions are defined as a satellite deep nodule found more than 2 cm from the main lesions or endometriotic lesions affecting several digestive segments [ 60 ].

The use of volume acquisition with 3D TVS permits a more accurate measurement and evaluation of the DIE lesion in different planes.

The pooled sensitivity and specificity of TVS for rectosigmoid endometriosis are reported as 90% and 96%, respectively, with similar results being provided by RES [ 56 ]. Guerriero et al., in a one-paired study, suggested that 2D-TVS was more sensitive but less specific than 3D TVS [ 61 ].

MR imaging of the pelvis is frequently performed for the detection of endometriosis, either as the second-line imaging examination (after US) for the detection/confirmation of endometriosis, in particular in deep infiltrating endometriosis, or as the initial examination in a patient for whom there is a high clinical suspicion for endometriosis and not ultrasound confirm [ 1 ].

MR imaging can be performed with either a 1.5-T or 3-T magnet, using a high-resolution phased-array surface coil for improved resolution. There is no consensus regarding whether to perform the examination around the timing of the patient’s menstrual cycle [ 13 ].

Patients are positioned supine on the scanner, with abdominal strapping after phased coil array placement. Fasting before the examination for 4 h is typically recommended in order to empty the upper gastrointestinal tract; the use of antiperistaltic agents is recommended to reduce motion artifacts caused by intestinal peristalsis. However, the type of agent (oral agents, nonoral agents), dose, and route (intramuscular, subcutaneous, or IV) is debated [ 18 ].

Patient preparation required a moderately filled bladder; this is required to change the angle of uterine anteversion, leading to better detection of implants in the anterior compartment. Moreover, a moderately filled bladder displaces the bowel superiorly, by reducing the artifacts from bowel motion [ 62 ].

For the evaluation of deep endometriosis it was suggested to introduce intra-vaginal aqueous gel to distend the vaginal cavity and better explore the vaginal fornices and the retrocervical area [ 62 ].

In the presence of symptoms that may be related to rectal involvement, gel may also be useful to distend the rectal\sigmoid bowel wall.

The typical imaging protocol [ 21 , 63 ] includes three T2 turbo-spin-echo (TSE)—weighted sequences (T2W) in different slice orientations (sagittal, coronal, and axial planes), followed by three T1-weighted (T1W) sequences in an identical imaging plane (TR 500 ms, TE 14 ms) without fat suppression and fat-suppressed T1W before and after intravenous injection of contrast media because the fat suppression is useful for the detection of subtle foci of hemorrhage, which may be obscured on non–fat-saturated images [ 64 ].

Use of contrast-enhanced imaging is primarily required to identify solid enhancing nodules within endometriotic cysts when malignant transformation is suspected.

Dixon technique or conventional in- and out-of-phase T1-weighted images are useful for the differentiation of fat-containing lesions, such as dermoid cysts from endometriomas, both of which have high signal on non–fat-saturated T1-weighted images [ 18 ].

No recommendation can be achieved for the use of DWI and SWI sequences.

Half-Fourier acquisition single shot turbo-spin-echo (HASTE) is recommended for the evaluation of uterine peristalsis because it enables multiphase and multislice image acquisition producing kinematic images for the evaluation of pelvic adhesions [ 1 ]. During the peri-ovulatory phase, uterine peristalsis is significantly reduced in subjects with endometriosis when compared to normal controls that may be due to increased, sustained contractions in endometriosis patients [ 65 ].

MRI Evaluation

At MR imaging the signal intensity of endometriotic lesions is a function of the quantity and age of the hemorrhage on the one hand and the proportion of endometrial cells and stroma on the other [ 66 ].

The lesions have a micronodular or microcystic appearance; however, cysts do not enlarge except in the ovary. Only pigmented lesions can be detected at non-contrast-enhanced MR imaging because of the presence of hemorrhage [ 67 ]. At MR imaging these small implants manifest as multiple round (cystic or nodular) lesions homogeneously hyperintense on fat-suppressed T1-weighted images, due to old hemorrhagic content, regardless of their signal intensity on T2-weighted images [ 67 ]. Involvement of peritoneal reflections over the cul-de-sac and the uterus may also manifest on contrast-enhanced fat-saturated T1-weighted images as diffuse peritoneal enhancement secondary to the inflammatory reaction induced by endometrial implants. Over time a fibrotic reaction may occur, thus leading to adhesions formation between pelvic structures [ 67 ].

T2W sequences are used for the evaluation of fibrotic lesions, notably those that involve the pelvic ligaments, retrocervical space, or prevesical recess [ 21 ].

They appear as speculated hypointense peritoneal strands arranged in confluent angles. Posterior displacement of uterus and ovaries, angulation of rectosigmoid colon and bowel loops, elevation of the posterior vaginal fornix, loculated fluid collections, and a hydrosalpinx may be indirect signs of adhesions [ 68 ].

At MR imaging both fibrous tissue and smooth muscle show intermediate signal intensity on T1-weighted images and low-signal intensity on T2-weighted images. Therefore, on T2-weighted images, solid endometriotic lesions appear as hypointense nodular structures with irregular or stellate margins due to fibrous tissue and smooth muscle proliferation. In certain cases, deep endometriotic lesions may also appear as irregular and hypointense soft-tissue nodular thickening on T2-weighted sequences, as it occurs when the disease involves the USL or the vaginal or rectal wall [ 66 ].

In some cases the glandular component can be predominant, compared to the fibrous tissue and in this case the MRI appearance will show high signal intensity of T2W images; in this case the use of contrast material can be useful because this will show enhancement, thus distinguishing it from intramural hemorrhage or necrosis [ 63 ]. Usually, endometrial glands without hemorrhage are not detectable on fat-suppressed T1-weighted images; so deep lesions may show homogeneous intermediate signal intensity on T1-weighted images. When red cell extravasation outside the glandular ducts into the surrounding stroma occurs, these small hemorrhages become visible as small hyperintense spots on fat-saturated T1-weighted images. After the intravenous administration of gadolinium, lesion enhancement may occur due to inflammatory reaction, glandular and fibrous tissue.

Owing to the possibility to perform a complete assessment of all pelvic compartments at one time, MRI represents the best imaging technique for preoperative staging of endometriosis [ 66 ].

Endometriotic lesions may affect the urinary tract in up to 20% of cases.

Bladder lesions appear as small masses of round or lobulated hypertrophic tissue covered by normal mucosa [ 67 ].

Bladder involvement is often multifocal, the trigone and the dome being the most frequently affected sites [ 23 ]. According to the degree of wall infiltration, bladder involvement may be classified as extrinsic or intrinsic. In extrinsic involvement, the most common form, implants are confined to the serosal surface or the surrounding connective tissue; in intrinsic involvement lesions infiltrate the muscular layer manifesting as mural masses [ 66 ].

At MR imaging bladder endometriosis may manifest as localized or diffuse wall thickening and signal intensity abnormalities [ 63 ]. The appearance is of low-signal intensity on T2-weighted and intermediate signal intensity on T1-weighted images, with or without spots of high signal intensity on T1-weighted images, representing hemorrhagic content. Sometimes, hyperintense foci on T2W images corresponding to the dilated endometrial glands may be found [ 66 ]. Implants minimally enhance after injection of a gadolinium-based contrast material [ 64 ].

The maximum lesion diameter varies between 1 and 5 cm. MRI reaches sensitivity up to 88%, specificity up to 99% and diagnostic accuracy of about 98% for the diagnosis of bladder endometriosis [ 23 ]. The differential diagnosis of bladder endometriosis includes urachal remnant, epithelial tumors (bladder carcinoma) and mesenchymal tumors (angiomas, leiomyoma) [ 23 ].

Urethral endometriosis is uncommon; direct implantation of endometrial tissues during procedures is hypothesized to be the etiologic mechanism [ 69 ]. In some cases, endometriosis may be mistaken for a urethral diverticulum and therefore a precise diagnosis is essential to facilitate optimal management. Usually, urethral involvement is observed as a contiguous extension from the bladder and the MRI findings are the same as those described for bladder endometriosis [ 64 ].

Ureteral endometriosis may be defined as any situation where endometriosis or surrounding associated fibrosis causes compression or distortion of the normal ureteral anatomy, even when hydroureteronephrosis is not yet present [ 70 ]. Ureteral endometriosis is quite uncommon, most often unilateral, with a left predisposition; bilateral involvement is present in approximately 10–20% of cases [ 71 ]. Ureteral involvement is often associated with an ipsilateral endometrioma or with a rectovaginal nodule larger than 3 cm. The distal ureter, 3–4 cm above the vesicoureteral junction, is the most common ureteral segment involved [ 71 ].

The symptoms can vary according to the type of nodule infiltration: indeed endometrial tissue can directly infiltrate the muscularis propria, lamina propria, or ureteral lumen causing symptoms that may be related to the pelvic endometriosis itself (dysmenorrhea, dyspareunia) or secondary to urinary tract involvement (flank pain, obstruction, and in some cases decline of renal function) [ 64 ]. Also in the ureteral endometriosis there are two major pathological types: extrinsic and intrinsic. Extrinsic endometriosis is the most common form (80%) of ureteral involvement and it represents endometrial glandular and stromal tissue within the submucosa and adventitia of the ureter [ 21 ]. In addition, scar tissue or fibrosis without true endometriotic invasion of the ureter may also be classified as extrinsic disease. In contrast, intrinsic endometriosis (about 20%) involves the uroepithelial and muscular layer. At MRI, ureteral endometriosis usually appears as hypointense solid nodules on T2W images with spiculated margins, that envelop the ureter, causing dilatation of the ureter upstream [ 72 ]. Extrinsic disease may be hypothesized when the interface of fat between the nodule and ureter is no longer visible. MR urographic techniques can be used to obtain three-dimensional reconstructed images from coronal volumetric excretory phase T1W data. The differential diagnosis of ureteral endometriosis includes ureteral invasion by cervical cancer [ 64 ].

Vesicouterine Pouch

The vesicouterine pouch or anterior cul-de-sac is a common site of endometriotic involvement [ 21 ]. These lesions are associated with anteflexion of the uterus and obliteration of the anterior cul-de-sac due to extensive adhesions between the peritoneum of the bladder fold and the uterus. At MR imaging deep endometriotic implants involving the anterior uterine serosa demonstrate infiltrative pattern with indistinct margins and show hypointense nodules on T2-weighted images, with small cystic areas that typically adhere to the anterior uterine surface, forming an obtuse angle with the vesical wall [ 72 ].

The ovaries are the most common site of endometriosis (20–40% of cases) [ 72 ]. They may be affected in two ways: (i) the endometriomas or chocolate cysts that are associated with ovarian enlargement, and which are caused by repeated episodes of hemorrhage; and (ii) small nodular superficial implants which may cause paraovarian fibrous scarring and adhesions [ 64 ] (Fig.  5 A–C).

An Example of multiple endometriomas of both ovaries, which appear enlarged and sharpened (ovarian kissing): A sagittal T1w fat sat imaging; B , C axial and sagittal T2w imaging

Peritoneal implants confined to the ovarian surface are often underdiagnosed at imaging due to their small size (< 5 mm) [ 66 ].

Endometriomas are frequently multilocular and bilateral (50% of cases). In MRI an endometrioma appears as a homogeneously hyperintense mass on T1W MR images; on T2W MR images, it appears as a low-signal intensity mass with areas of high signal intensity [ 67 ] (Fig.  6 A–F). Endometriomas have a wall with a variable appearance (from thin to thick and fibrotic) and they usually contain dark/brown semi-solid material that represents the degenerated blood products (the so-called ‘‘chocolate cyst’’) [ 67 ] (Fig.  7 A–E). Because the endometriomas contain blood products of different ages and concentrations, they may show a variable appearance, in fact as free water in the cyst is resorbed, the iron concentration increases along with the viscosity of the contents of the cyst: this condition determines the ‘‘shading effect’’. Shading is present when a cyst, hyperintense on a T1W image, shows a gradient from hypointense to hyperintense on a T2W image. Shading can range from faint, dependent layering to complete signal void, according to the concentration of blood products [ 64 ]. It reflects the chronic nature of endometriomas and is the result of cyclic bleeding occurring over time. Old blood products contain high iron and protein concentrations which determine a decrease in T2 relaxation time. Therefore, on T2-weighted images endometriomas will show a gradual loss of signal within the lesion with low-signal intensity till complete signal void in the declivous portion.

An example of ovarian endometriosis: A T1w imaging; B , C axial and sagittal T2w imaging; D , E axial and coronal T2 fat sat imaging; F T1w imaging after contrast administration. Hyperintensity in T1w is typical of a recent bleeding

An example of endometrioma: A T1w imaging; B , C axial and coronal T2w imaging; D axial T2 fat sat imaging; E axial T1w imaging after contrast administration. It’s visible a double fluid–fluid level, indicating different bleedings

The most specific pathologic feature of endometrioma is the thick fibrous capsule containing a cluster of hemosiderin-laden macrophages due to repeated hemorrhage [ 66 ].

In certain cases, the ovaries may be joined together behind the uterus in the pouch of Douglas due to adhesion formation between the adjacent peritoneal surfaces, a sign described at US as B kissing ovaries ^ and suggestive of severe pelvic endometriosis [ 73 ].

Togashi et al. found that an extremely sensitive sign for the presence of an endometrioma was the presence of a cyst hyperintense on T1W images and the presence of shading on T2W images [ 74 ]. Another criterion is to observe multiple hyperintense cysts on T1W images (and T1W fat-suppressed images) regardless of their signal intensity on T2W images (Fig.  8 A–F).

An example of endometriotic cyst: A axial T1w imaging; B , C axial and coronal T2w imaging; D axial T2 fat sat imaging; E , F axial and coronal T1w imaging after contrast administration

The differential diagnosis of endometriomas includes lesions with high signal intensity on T1-weighted images: dermoids, mucinous cystic neoplasms, and hemorrhagic masses. Fat-saturated T1-weighted sequences are helpful to rule out a fat-containing lesion (such as dermoids) and to confirm the presence of blood [ 75 ]. Mucinous lesions may show hyperintensity on T1-weighted images, but signal intensity is lower than that of blood.

It is possible to recognize and differentiate dermoids from endometriomas by the presence of chemical shift artifact and signal drop-out on the fat suppression image. Thus, on a T1-weighted frequency selective fat saturation sequence, the mature cystic teratoma will be low in signal, whereas an endometrioma will have high signal [ 64 ].

Hence, the most challenging differential diagnosis is with other hemorrhagic masses. To differentiate endometriomas from functional hemorrhagic cysts is important in order to prevent unnecessary surgical interventions. Functional hemorrhagic cysts (i.e., hemorrhagic follicular cysts and hemorrhagic corpus luteum cysts) are usually unilocular and unilateral, do not display shading on T2-weighted images, and mostly disappear on follow-up examinations (generally in 4–6 weeks), while endometriomas are usually multilocular and bilateral [ 68 ].

The role of DWI sequences in differentiating endometriomas from functional hemorrhagic ovarian cysts is still debated. Balaban et al. found significantly lower ADC values in endometriomas compared with functional hemorrhagic ovarian cysts in all b values [ 76 ]. Large lesions with wall nodularity, thick septations and enhancing solid components may be suggestive of malignancy.

Fallopian Tubes

Endometriotic involvement of the fallopian tubes is strongly associated with infertility. Serosal or subserosal implants involves the peritoneal surface of the fallopian tubes, where repeated hemorrhages lead to fibrosis and retraction of the tube with hydrosalpinx. Intraluminal implants determine cyclic hemorrhage thus causing hematosalpinx [ 66 ].

Moreover, an association has been described between the endometriosis in the fallopian tubes and a predisposition to endometrial malignancies such as clear cell carcinoma and endometrioid carcinoma [ 67 ].

At MR imaging hematosalpinx appears as a tortuous enlarged tubular adnexal structure filled with hemorrhagic fluid. Endoluminal content shows high signal intensity on fat- suppressed T1-weighted images and intermediate signal intensity, (40% of distended tubes in endometriosis have hyperintense contents) with or without internal fluid–fluid level, on T2-weighted images [ 77 ]. According to Siegelman the presence of T1-weighted hyperintensity within a dilated fallopian tube is suggestive of endometriosis [ 78 ].

In addition, it is atypical to see T2 shading within the lumen of the distended fallopian tube even when there is high signal on T1-weighted images [ 78 ]. T2 shading is not seen because of the fact that the endometriotic implants are mostly along the surface of the tube and not within the lumen of the tube, such that the chronic bleeding within the implants leads to adhesions along the tubal surface, but not within the lumen. The differential diagnosis of a hematosalpinx on MR imaging includes PID or fallopian tube malignancies. Pyosalpinx of PID can be differentiated by the clinical signs of infection (fever, white count) [ 18 ].

On MR imaging, hyperemia surrounding the fallopian tube with stranding in the adjacent fat would suggest a pyosalpinx. Fallopian tube carcinoma demonstrates solid, enhancing internal nodules within the fallopian tube and tends to occur in an older demographic group [ 43 ].

Uterus and Vagina

The most common localization of ectopic endometrial tissue within the uterus is the adenomyosis. Whereas it is important to remember that uterine involvement by endometriosis is usually subserosal, sometimes it is possible to find nodules of endometriosis in the serosal surface of the uterus [ 64 ].

Vaginal endometriosis is usually associated with implants in other pelvic locations, mostly retrocervical and rectal lesions; seldom isolated involvement of the vagina may occur. The upper one-third of the vagina and the posterior fornix are the most commonly affected sites. Generally, the vaginal wall implants show a thickened or nodular appearance [ 21 ], but may also have a polypoid structure. At MR imaging vaginal endometriotic implants show low-signal intensity on T2-weighted images. They often have a multiloculated internal appearance because of the presence of cystic areas [ 66 ]. These locules can show hyperintense content on T1-weighted images due to subacute blood products. Polypoid variant may have a T2 hypointense rim corresponding to surrounding fibrous tissue associated with endometriosis [ 79 ]. Rectovaginal fistulation represents a complication of vaginal endometriosis. Differential diagnosis includes epithelial neoplasms arising from the uterine cervix or vaginal wall [ 66 ].

Uterine Ligaments

At MRI the round ligaments can be identified as thin structures with hypointense fibrous signal on T1- and T2-weighted images, extending from the uterine horns to the pelvic side- wall, passing anteriorly to the external iliac vessels. They have an intra- and an extra-pelvic portion, the latter being the distal part of the ligament in the canal of Nuck [ 80 ]. When involved by endometriosis, round ligaments appear thickened (more than 1 cm), nodular, shortened and irregular. Usually endometriotic implants are a mixture of fibrous tissue and hemorrhage. Fibrous tissue shows hypointense signal on T1- and T2-weighted images; small hemorrhagic foci displays hyperintense signal on fat-suppressed T1-weighted images [ 66 ]. The presence of free fluid around the intra-pelvic portion of the round ligaments may represent an indirect sign of endometriosis [ 80 ].

Endometriosis of the broad ligaments usually manifests as thickening and nodularity of these peritoneal folds extending between the uterus and the lateral walls of the pelvis. These nodules are visible as hypo-intensity signal in T2 sequences and after administration of contrast material it is possible to observe a diffuse peritoneal enhancement secondary to the inflammatory reaction incited by microscopic endometrial implants on contrast-enhanced fat-saturated MRI [ 64 ].

Uterosacral ligaments (USL) are the most frequent location of deep endometriosis. Bilateral USL involvement is often associated with other posterior deep endometriotic locations, mostly the rectosigmoid colon [ 81 ]. At MR imaging normal USL are depicted as thin, regular, semicircular hypointense cords that originate from the lateral aspect of the uterine cervix and the vaginal vault and course dorsocranially toward the sacrum [ 21 ]. USL endometriosis is depicted as nodularity within the ligament or as unilateral or bilateral hypointense thickening of the ligament, with regular or irregular margins [ 21 ]. The proximal medial portion of the USL is most commonly affected by endometriosis.

According to Bazot et al. thin-section oblique axial T2-weighted sequences (3 mm thick, perpendicular to the long axis of the cervix) can improve the capability of conventional MRI to assess USL endometriosis [ 81 ].

Saba et al. suggested that the diagnosis of endometriosis of the USL is simple when ligaments are involved together with the torus uterinus, whereas, when there is only a thickening or an asymmetric nodular irregularity the involvement of the USL can be difficult [ 64 ].

In a recently published meta-analysis the sensitivity and specificity of MRI for the diagnosis of endometriosis of USL were 85% and 80%, respectively [ 82 ].

Retrocervical Area

The retrocervical area is a virtual extraperitoneal space behind the cervix, located above the rectovaginal septum [ 21 ]. It is a common site of deep pelvic endometriosis. Retrocervical implants are often associated with USL involvement and with the retroversion of the uterus [ 83 ].

Deep endometriotic lesions of the retrocervical area frequently appear as ill-defined infiltrative tissue, hypointense on T2-weighted images, extending from the posterior uterine serosa to the retrocervical region [ 21 ]. Nevertheless, some lesions may contain abundant glandular component and little fibrotic reaction, thus showing high signal intensity on T1-weighted images and variable signal intensity on T2-weighted images [ 21 , 63 ]. The solid glandular component enhances after intravenous administration of contrast material [ 63 ].

Del Frate et al. identified a condition they called ‘‘hourglass-shaped’’ lesions that are found in 25% of cases and are due to posterior extension of a posterior forniceal lesion toward the anterior rectal muscularis. These lesions are usually larger than 3 cm, with a greater risk of extension to the rectal wall [ 63 ].

In a recently published meta-analysis the sensitivity and specificity of MRI for the diagnosis of endometriosis of the pouch of Douglas were 89% and 94%, respectively [ 82 ].

The differential diagnosis of retrocervical lesions includes peritoneal metastases from intraperitoneal malignancies (i.e., gastrointestinal and ovarian neoplasms). Peritoneal metastases usually show intermediate to high signal intensity on T2-weighted images and, as the primary cancer site, high signal intensity on DWI; moreover, ascites and a tumor mass into the abdominal cavity may be identified [ 84 ]. On the other hand, solid endometriosis shows low-signal intensity on T2-weighted images [ 66 ].

Rectovaginal Pouch

The rectovaginal pouch is the anatomical region located between the posterior vaginal wall and the anterior rectal wall. It extends from the deepest part of the pouch of Douglas to the top of the perineal body [ 66 ]. The inferior two thirds of this space constitute the rectovaginal septum, a thin membranous partition usually filled with fat [ 21 ]. Usually rectovaginal implants represent extensions from retrocervical or posterior vaginal lesions.

In MR I , nodules of endometriosis affecting the rectovaginal pouch usually appear as hypointense nodules on both T1W and T2W MRI images with signal intensity close to that of pelvic muscle [ 85 ]. Sometimes, foci of endometriosis may also have an abundant glandular component and discrete fibrotic reaction. In such cases, the endometriotic foci are hyperintense nodules on T1W and fat-saturated T1W MRI images, irrespective of their appearance on T2W MRI images. Moreover, the solid glandular component shows variable enhancement after the intravenous administration of contrast material [ 64 ].

In normal conditions the MRI depicts the rectovaginal septum as a hyperintense signal area in T1W and T2W images whereas nodules of endometriosis affecting the rectovaginal septum usually appear as hypointense nodules on both T1W and T2W MRI images [ 64 ].

In a recently published meta-analysis the sensitivity and specificity of MRI for the diagnosis of rectovaginal septum endometriosis were 82% and 77%, respectively [ 82 ].

Rectosigmoid Colon

Among the bowel segments the rectosigmoid is the most commonly involved by endometriosis (65.7%), followed by vermiform appendix, terminal ileum, cecum and descending colon, in order of frequency [ 86 ]. Rectosigmoid endometriosis is often associated with other pelvic locations and with a second intestinal lesion in 55% of cases [ 72 ].

The rectosigmoid endometriosis may cause adhesions, bowel strictures, or intestinal obstruction may result from the inflammatory response to cyclic hemorrhage. The implants are usually serosal but can sometimes involve the subserosal layers and cause thickening and fibrosis of the muscularis propria. Usually, an intact overlying mucosa is present, since the implanted tissue only rarely invades through to the mucosa [ 21 ].

Typically, endometriotic lesions infiltrating the anterior rectal wall have a characteristic fan-shaped configuration (or a pyramidal shape, with the base adhering to the rectal wall and the apex oriented anteriorly toward the retrocervical region). The core of the lesion shows isointense signal compared to muscle on T2-weighted and T1-weighted sequences and at histopathology corresponds to thickening and distortion of the muscularis propria and smooth muscle hyperplasia [ 66 ]. The overlying layer, hyperintense on T2-weighted images, at the luminal side of the bowel wall corresponds to (sub)mucosal thickening, as a consequence of non-specific inflammation with or without infiltration of endometriosis [ 86 ]. When the longitudinal extent of the parietal lesion along the bowel wall is short, a pattern of intraluminal endophytic growth, called mushroom cap, may be observed [ 87 ].

When nodules of endometriosis are localized in the retroperitoneal section frequent concomitant findings are the adherences that identify fibrotic tissue originating from the nodules of endometriosis and involves the closest organs. Sometimes the adherences determine traction of the affected organs [ 88 ]. This is an important finding because it can be considered an indirect sign of endometriosis.

In a recently published meta-analysis the sensitivity and specificity of MRI for the diagnosis of rectosigmoid colon endometriosis were 83% and 88%, respectively [ 82 ]. MR imaging is useful to predict infiltration of the muscular layer of the bowel with a sensitivity of 100% and specificity of 75%. On the other hand, it is of limited value in diagnosing (sub)mucosal infiltration, as (sub)mucosal thickening may be caused by edema without infiltration of endometriosis. Nevertheless, extensive irregularities of the (sub)mucosal layer may raise suspicion of (sub)mucosal involvement [ 86 ]. Differential diagnosis includes rectal cancer and metastatic implants to the bowel [ 66 ].

Conclusions

Endometriosis is a chronic condition that affects women during the reproductive lifespan. Diagnosis of endometriosis is complex as it must take into account non-pathognomonic clinical symptoms and non-specific laboratory tests. The physical examination and above all the different imaging techniques, in particular US and MRI, constitute the gold standard for diagnosis. The role of the radiologist is fundamental both in the diagnosis of endometriosis, especially in the deep sites that cannot be seen with ultrasound, and in planning the type of therapeutic approach. A multidisciplinary study is essential for the management of these patients from both a clinical and surgical point of view.

Papers of particular interest, published recently, have been highlighted as: • Of importance, •• Of major importance

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Testini, V., Eusebi, L., Grechi, G. et al. Imaging of Endometriosis: The Role of Ultrasound and Magnetic Resonance. Curr Radiol Rep 10 , 21–39 (2022). https://doi.org/10.1007/s40134-022-00393-x

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How to Deal With Endometriosis Pain

By Dennis Thompson HealthDay Reporter

SATURDAY, March 9, 2024 (HealthDay News) -- Endometriosis causes crippling pain in women, with some spending up to a month of every year debilitated by it.

“We’re talking about pain that’s beyond ‘I took two ibuprofen and went to work,’” said Dr. Kristin Riley , chief of minimally invasive gynecologic surgery at Penn State Health Medical Center. “We’re talking about pain that keeps people from living their lives.”

The condition involves tissue normally found in the uterus instead growing in the ovaries, bowels, bladder and elsewhere, Riley said. It affects roughly 190 million women around the world.

The pain caused by endometriosis ranges from endurable to excruciating, Riley said. Sometimes women can shrug it off, while at other times leaving the house or getting out of bed isn’t an option for days at a time.

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There’s no cure, but doctors have become adept at diminishing its agony, Riley said. Women with endometriosis or chronic pelvic pain now have a wealth of options to choose from, including some geared to very specific kinds of pain.

“It’s not a one size-fits-all approach,” Riley said in a Penn State news release. “It’s very individualized.”

Pain during a period doesn’t necessarily mean there’s a problem, Riley said. But when it becomes debilitating, a woman should speak with her doctor.

Some questions Riley asks of her new patients include what the pain is like, where it is coming from and what it keeps them from doing.

“Some people have this cramping pain,” Riley said. “Some people have sharp shooting nerve pain or muscle pain. Some people have something that starts out as bad period pain, and then it moves on to other organs – gastrointestinal pain, bladder pain, abdominal wall pain, back pain -- or all of those things.”

The organs in a woman’s pelvis all function in a cavity about five inches wide, meaning that when one organ is inflamed, the problem often affects others. Women with endometriosis pain often discover bladder or bowel aches, as well as problems with sexual function and fertility.

Potential treatments include:

Anti-inflammatory drugs. These medicines are typically the first line of defense, to decrease inflammation in organs affected by endometriosis.

Hormone therapy. Hormone therapy drugs used to suppress periods are helpful for some in stemming endometriosis pain. Estrogen can slow the growth of the tissue outside of the uterus and control pain related to periods and flare-ups.

Neuropathic pain medications. These pain medicines target the nerves that transmit pain to the brain. These drugs are sometimes used to treat mental health problems.

Cannabidiol (CBD). CBD creams, pills and oil droplets have become widely available as pain relievers for people with endometriosis. Most haven’t been tested, but some patients and doctors say CBD offers relief with relatively few side effects.

Transcutaneous electrical nerve stimulation (TENS). Some patients find relief through a mild electrical current passed through leads attached to their muscles. The practice relaxes tissues and decreases pain, Riley said.

Yoga and mindfulness meditation. Holistic Eastern medicine techniques are offering some benefits for women with endometriosis. Yoga specially geared for endometriosis patients can decrease pain and stress, as can mindfulness meditation involving breathing exercises. 

Diet. Some patients find relief if they alter their diet to avoid foods that trigger GI reactions, as these reactions can cause pain flares related to endometriosis. “Some patients are cutting out dairy, red meat, processed food and foods high in sugar content,” Riley said.

One last note: While opioids are an option, doctors are hesitant to prescribe them due to the risk of addiction and misuse, Riley said.

“We do have some patients that are treated with them for chronic pain,” Riley said, despite the risks.

Another problem is that opioids deaden the mind “so you don’t care about the pain,” rather than reducing inflammation or targeting what’s actually causing it, Riley added.

SOURCE: Penn State Health, news release, March 6, 2024

Copyright © 2024 HealthDay . All rights reserved.

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Endometriosis: A Review of Clinical Diagnosis, Treatment, and Pathogenesis

Saurabh chauhan.

1 Clinical Embryology, School of Allied Health Science, Datta Meghe Institute of Medical Sciences (DU), Wardha, IND

2 Anatomy, Wardha Test Tube Baby Center, Datta Meghe Institute of Medical Sciences (DU), Wardha, IND

Vaishnavi Chauhan

Aditya kathane.

Endometriosis is a condition that affects women of reproductive age, and it is distinguished by the development of endometrial-like tissue outside the uterine cavity. It is frequently accompanied by persistent pelvic discomfort and infertility. This investigation looks into recent findings on clinical manifestation to help doctors and improve women's health. PubMed and Google Scholar were used to review on clinical diagnosis of endometriosis. The search strategy contained the terms “endometriosis” and “clinical diagnosis.” All research articles published between 1960 and 2021 were included in the search. The findings were then categorized to summarize the evidence. There was a total of 29 instances of endometriosis discovered. The patients' ages varied from 20 to 45 years old, with a median of 28.8 years and a mean of 29.4±7.7 years. Dysmenorrhea is a common disorder among adolescent girls experiencing various physical and emotional symptoms which have a detrimental influence on their quality of life. In this study, scar endometriosis was shown to be the more common variety of endometriosis, with 50% of cases predominantly developing at the lower segment cesarean section (LSCS) scar site. As a result, women with endometriosis are more likely to have miscarriages, and the quality of their embryos declines as a result.

Introduction and background

Endometriosis is the most perplexing gynecological condition [ 1 - 3 ]. Endometriosis influences 10%-15% of all reproductive-age females and 70% of women with persistent pelvic pain [ 4 ]. The ovaries and pelvic peritoneum are the most common sites for developing endometriotic lesions. Endometriotic lesions can also develop in other places including the fallopian tube, abdominal wall, bowels, cervix, bladder, and vagina [ 5 , 6 ]. The pathophysiology of endometriosis and pain is poorly known, with most gynecologists believing that inflammation is a crucial source of irritation in endometriosis [ 7 ]. After successful surgery, some women seem to be “cured” of the disorder, but the majority will have a recurrence of symptoms. Endometriosis costs roughly 1 to 2 lakhs per woman in India, according to a survey [ 8 ]. The uterosacral ligaments, the upper third part of the posterior vaginal wall, the rectovaginal space, the intestine, and the urinary system are frequently involved in the latter [ 9 ]. Researchers have previously looked at apoptosis, cell cycle changes, and granulosa cell oxidative stress as indicators of oocyte quality as a source of endometriosis subfertility [ 10 - 12 ].

Endometriosis is a female reproductive system disorder where the endometrium-like tissue develops outside of the uterus; it usually affects the ovaries and peritoneum, causing premenstrual discomfort and dysmenorrhea [ 13 , 14 ]. The most widely recognized explanation of endometriosis is that endometrial tissue is implanted in the peritoneal cavity by retrograde menstruation. The first theory describing the origin of endometriosis is the retrograde menstruation theory. According to this idea, endometriosis develops when sloughed endometrial cells and debris after menstruation travel retrogradely down the fallopian tubes and enter the pelvic cavity. 76%-90% of women having patent fallopian tubes experience retrograde menstruation, albeit not all of these women have endometriosis [ 15 ]. Endometrial cell resorption into the abdominal wall during menstrual flow is a common occurrence in 90% of menstrual females with patent fallopian tubes, even though it is only seen in those with hormonal or immunological issues [ 16 , 17 ]. The peritoneal fluid of women with endometriosis has higher amounts of macrophages, T-lymphocytes, and B-lymphocytes, which are more susceptible to apoptosis [ 18 , 19 ].

Clinical diagnosis of endometriosis

Endometriosis lesions are most frequently encountered in the following regions like fallopian tubes, uterus outer surface, ovaries, and the ligaments which surround the uterus. Lesions from endometriosis can range in size and frequently take the form of nodules or cysts. The majority of them are blue, black, and brown in color. They can, however, sometimes occasionally be white, red, or transparent [ 20 , 21 ]. Infertile women with minor or mild endometriosis have had the condition detected more frequently during in vitro fertilization (IVF) and embryo transfer (ET) cycles than those with moderate or severe endometriosis [ 1 , 22 - 24 ]. With a diagnostic age of 28 years, endometriosis predominantly affects women who are of reproductive age, which may be understood by the estrogenic milieu, which is strongly implicated in its genesis [ 25 ]. Extrauterine endometrial cells on laparoscopy are generally enough for histologic confirmation [ 26 ]. Cystic endometriomas might be reliably recognized utilizing transvaginal ultrasonography, while more modest endometrial implants are not detected [ 27 , 28 ].

Infertility and severe pelvic discomfort are the two major clinical risk factors for endometriosis [ 29 - 32 ]. The etiology of infertility in women with minor or mild endometriosis is less understood. However, it might be linked to a greater prevalence of malformed oocytes, faulty embryos, or unsuccessful implantation [ 33 ]. According to several studies, tall women with low Body Mass Index (BMI) appear at a greater risk of developing endometriosis because they have short menstrual cycles, are more likely to have cervical canalization problems, and decreased germ cell endowment [ 34 ]. Endometriosis has also been found to be less common among women who have been pregnant [ 29 ]. This might be owing to pregnancy's protective impact, or it could be due to endometriosis patients' lower fertility, as endometriosis risk is inversely associated with the number of term pregnancies [ 29 , 35 , 36 ].

Endometriosis was found in 19% of women with persistent pelvic discomfort at the point of surgery [ 37 , 38 ]. Dysmenorrhea, intermenstrual discomfort, and dyspareunia are common symptoms of pelvic pain. The most prevalent symptom is dysmenorrhea, which, while not predictive, is highly indicative of endometriosis in its severe form [ 39 ]. Dysmenorrhea is frequently progressive, with discomfort beginning before menstrual flow and lasting for the whole of the menstrual cycle and possibly for many days after that [ 40 , 41 ]. Endometriosis of the rectovaginal septum and cul-de-sac are common causes of dyspareunia [ 42 ]. Dysmenorrhea and dyspareunia are more likely to be caused by endometriosis if they appear after years of pain-free menses and coitus [ 43 , 44 ]. The overproduction of uterine prostaglandins aids pathogenesis. Urinary tract endometriosis can induce hematuria, urgency, dysuria, and frequency [ 45 , 46 ].

Dysmenorrhea

During menstruation, dysmenorrhea is a medical disorder characterized by discomfort around the pubic bone and lower abdomen [ 47 , 48 ]. Dysmenorrhea is related to a limitation of activity and leaves from school or work, precisely when it is severe [ 49 ]. Mental preparedness and suitable lifestyle changes, such as frequent physical activity, can help control dysmenorrhea [ 50 ]. Dysmenorrhea can be primary or secondary. Primary dysmenorrhea is a kind of dysmenorrhea that occurs in teenagers shortly after menarche and is caused by a lack of underlying macroscopic pelvic disease [ 51 ]. Early menarche, lengthier menstrual cycles, high menstrual flow, and a family history of dysmenorrhea are all risk factors [ 52 , 53 ].

Dyspareunia

Dyspareunia, or pain during penetration, occurs during sexual activity. Deep and superficial dyspareunia are the two most common kinds of dyspareunia [ 54 ]. Deep dyspareunia refers to the expansion of discomfort into the deeper regions of the vagina or lower pelvis, whereas superficial dyspareunia is restricted to the vulva or vaginal entrance. Profound penetration is typically correlated with deep dyspareunia [ 55 ]. Deep dyspareunia in endometriosis has a complicated etiology that might involve direct endometriotic lesions, concomitant diagnosis, and other factors [ 56 ]. Deep dyspareunia affects 50% of all female patients, a disorder that affects 10% of reproductive-age females and is linked to the poor sexual quality of life. Other forms of pelvic pain, psychiatric comorbidities, and concomitant pain diagnoses can occur in women with endometriosis [ 55 , 57 ].

Pathogenesis of endometriosis

Endometriosis pathogenesis suggests that the disease's etiology is complicated and multifaceted, involving genetic, hormonal, immunological, and environmental factors [ 58 ]. The pathogenesis of superficial endometriosis and the genetic factors that prevent ectopic lesions from being removed and allow for peritoneal remodeling may both be triggered by retrograde menstruation. These are critical for endometriosis lesion growth [ 59 ]. Endometriosis is spread by a change in the peritoneal fluid composition due to biological, hormone, and environmental factors [ 60 , 61 ]. Deep nodule tumors that are not generally eliminated during menstruation, might be quickly produced in a baboon model by transplanting basal endometrial tissue [ 62 , 63 ]. Endometriosis progresses due to genetic changes that damage the cell, since females with endometriosis have an abnormal endometrial cellular response, favoring extrauterine adhesion and proliferation [ 64 ]. Endometriosis has a genetic inheritance pattern that is believed to include numerous loci, as well as some chromosomal areas that have been linked to the endometriosis phenotype [ 65 ]. Genetic factors, both inherited and acquired, might predispose females to the adherence of abnormal endometrial tissues to the peritoneal epithelium as well as the resistance of immune clearing of these lesions [ 66 ]. Endometrial fragments that are still viable are pushed into the fallopian tubes by a pressure gradient caused by dyssynergic uterine contractions [ 67 , 68 ]. They can implant, develop, and infiltrate pelvic bones when they enter the peritoneal cavity [ 69 , 70 ]. Hyperalgesia is a symptom of nerve pain, which is generally caused by nerve damage or inflammatory stimulation. Endometriotic stroma cells typically invade sensory nerve fibers in deep endometriosis [ 71 , 72 ].

We focused on pelvic endometriosis in this study since it is the most prevalent kind of endometriosis, and it usually affects women throughout their reproductive years. PubMed and Google Scholar were used to conduct a review of the clinical diagnosis of endometriosis. In the titles or abstracts of papers, the search strategy contained the terms “endometriosis” and “clinical diagnosis.” The data from each clinical diagnosis document were extracted and categorized.

In this study, there were 29 cases of endometriosis in total. The age range of the patients was 20 to 45 years, with a mean age of 29.4±7.7 and a median age of 28.8 years. The scar endometriosis (16 cases) involving the anterior abdominal wall at the lower segment cesarean section (LSCS) scar site, ovarian endometriosis (10 cases), urinary bladder endometriosis (two cases), and bowel endometriosis (one case) involving the sigmoid colon. According to the data, ovarian endometriosis and scar endometriosis are the two types of endometriosis that are most common in women aged 20 to 35. Scar endometriosis has been the most frequent kind of endometriosis in this research, accounting for 50% of all cases. In 14 of the 16 patients, there was a mass in the LSCS scar, which was identified by preoperative Fine Needle Aspiration Cytology (FNAC) in nine instances (56.25%) and histological analysis of excised tissues in seven cases (43.75%). The second most prevalent condition was ovarian endometriosis, which accounted for 37.5% of cases, with one instance being bilateral and another showing torsion. Bowel endometriosis with only one case involving the sigmoid colon accounted for 4.3% of cases, whereas two cases with urinary bladder endometriosis accounted for 8.3%.

Treatment of endometriosis

The goal of medical therapy for endometriosis has been to change the menstrual period hormonally to induce a pseudopregnancy, pseudo-menopause, or persistent anovulatory state [ 73 ]. The recommended daily dose of danazol for the treatment of endometriosis is 600-800 mg; even so, the dose has significant steroid side effects, including increased hair growth, changes in mood, an irreversible deepening of the voice, bad impacts on serum lipids, and, in rare cases, irreversible and life-threatening liver injury [ 74 ]. Endometriosis is typically treated with progesterone-based medications. They induce endometrial cells to decidualize, resulting in atrophy. Abnormal uterine bleeding, vomiting, breast discomfort, and depression are all possible side effects [ 75 , 76 ]. Hypoestrogenism's adverse effects include vaginal heavy bleeding, vaginal dryness, reduced libido, breast discomfort, sleeplessness, and depression [ 77 ]. Endometriosis has been treated with a variety of hormones and medicines. Hormone therapy often prevents ovulation by preventing the ovaries from releasing hormones, including estrogen. This could aid in reducing the rate of local development and activity of the endometrium and endometrial lesions. Because of their negative side effects, several hormones, such as methyltestosterone and estrogen, have been phased out. Other medications have been inadequately investigated, including clomiphene, tamoxifen, and the anti-progestational drug mifepristone [ 78 ]. Laparoscopic surgery is used to surgically diagnose endometriosis. A laparoscope, a narrow viewing tube, is inserted into the belly through a tiny incision during laparoscopy. For a second entrance for the surgical tools, a second incision may be created in the lower abdomen. Your doctor can view the outside of the ovaries, uterus, fallopian tubes, and other organs up close using a laparoscope. Surgical tools for removing scar tissue or obtaining tissue samples can also be attached to the laparoscope [ 79 ]. For ovarian cysts greater than 4 to 5 cm in diameter, laparoscopic endometrioma removal is suggested [ 80 ]. Endometriosis has been treated with a range of devices, from monopolar cautery and scissors to a wide variety of lasers and ultrasonic scalpels [ 81 ]. Endometriosis pain is treated surgically by interrupting the brain circuits that carry pain signals [ 82 ]. Various considerations should be taken, including the best method of gaining access to the pelvis and abdomen, which can be accomplished by laparoscopy or laparotomy. Laparoscopy is less expensive and takes less time to recuperate. Magnetic resonance imaging (MRI) scan not only shows morphologic defects in the bladder but can also identify other common areas, such as the uterosacral joints, where ultrasonography is less accurate [ 83 ].

Endometriosis affects people and cultures all over the world; however, there are significant delays in diagnosis. More illness awareness in inpatient healthcare should result in earlier diagnosis, less suffering, and increased productivity [ 84 , 85 ]. Gravidity, endometriosis in the family, dyspareunia, tiredness, dysmenorrhea, pelvic surgery, diarrhea, pelvic discomfort, and premenstrual spotting are all risk factors for endometriosis [ 86 ]. Several explanations for the connection between endometriosis and infertility have been claimed, but despite substantial investigation, no conclusion has been achieved. These mechanisms include distorted pelvic anatomy, altered peritoneal function, endocrine, and ovulatory abnormalities, and altered hormonal and cell-mediated functions in the endometrium [ 87 , 88 ]. Increased obstetric surgery results in the direct mechanical implantation of endometrial cells, which is one of the major risk factors for scar endometriosis [ 89 ].

When a patient experiences dysmenorrhea after experiencing pain-free menstrual cycles for years, endometriosis should be suspected [ 90 ]. Endometriomas having a maximal diameter of 3-4 cm are best treated through transvaginal cystectomy. Less than 1% of women develop ovarian endometriosis malignancy, which most frequently manifests as endometrioid/clear cell carcinoma [ 91 ]. Between 1% and 5% of women with endometriosis have urinary tract involvement, with the urinary bladder being the most commonly affected, followed by the ureter, urethra, and kidney [ 92 , 93 ]. In 3%-37% of instances, endometriosis was known to have an impact on the digestive system, with the recto-sigmoid colon as the most often affected area [ 94 ]. Although comparable findings have been documented in cancer patients, the link between diagnostic delay and health care funding for endometriosis is unique [ 95 - 97 ]. The majority of endometriosis patients have normal pelvic findings; hence a laparoscopy is required to make a conclusive diagnosis. It is likely that ultimately a combination of biochemical indicators and clinical evaluation will lessen the requirement for surgical confirmation, even if no single laboratory test has demonstrated proven clinical usefulness [ 98 , 99 ]. Endometriosis is more frequent among Caucasian, middle-aged, upper-class women who are ambitious. This could happen because these women have more access to medical treatment and diagnostic procedures like laparoscopy [ 100 ]. This might be because these women have easier access to medical treatment and diagnostic testing like laparoscopy [ 101 , 102 ]. As endometriosis frequently exhibits symptoms that resemble those of other disorders and cause a diagnostic delay, early suspicion of the condition is crucial for prompt diagnosis. In addition to a patient's medical history, secondary centers with access to further investigations may need to be referred from the main health care level [ 103 , 104 ].

Ovarian Endometriosis

Ovarian endometriomas account for 35% of all benign ovarian cysts and are seen in 17%-44% of female patients [ 105 ]. Endometrial cell growth may be induced by ovarian follicular fluid [ 106 ]. Left ovary endometriomas are more prevalent than right ovary endometriomas [ 107 ]. The amount of normal ovarian in the swollen ovarian cortex was decreased in endometrioma patients' ovarian cortical tissue, a result not seen in other benign cysts to a similar extent [ 108 ]. The ovary with endometrial cysts exhibits lower reactivity to exogenous gonadotropin activation, with more follicular atresia, and a higher rate of follicular atrophy [ 109 ]. The most prevalent histologic forms of ovarian cancer resulting from ovarian endometriosis are endometrioid adenocarcinoma and clear cell carcinoma [ 110 , 111 ].

Scar Endometriosis

Scar endometriosis occurs when endometrial tissue is implanted directly in scars during surgery [ 112 ]. Other surgical disorders such as hematoma, hernia, scar tissue, neuroma, abscess, granuloma, or even metastatic cancer can easily be coupled with scar endometriosis [ 113 , 114 ]. The presence of morphological and physiological stroma and endometrial gland beyond the uterine cavity is a persistent gynecologic condition [ 115 ]. The kidneys, pleura, bladder, lungs, colon, lymph nodes, omentum, and abdominal wall are all common locations for extra pelvic endometriosis [ 116 ].

Urinary Bladder Endometriosis

Extragenital endometriosis most commonly affects the gut and urinary system [ 117 ]. The urinary bladder is a rare location of endometrial localization, with just around 1% of people that are suffering from the illness having lesions affecting the urine system [ 118 ]. To avoid kidney function loss, urinary tract endometriosis must be diagnosed and treated early. For women who complain of bladder pain but have a negative urine test, the doctor may not examine if the discomfort is cyclic or whether bladder endometriosis is a possibility. Endometriosis in the urinary system is uncommon, occurring in about 1%-6% of females with initially diagnosed endometriosis [ 119 ].

Conclusions

Long-term conditions like endometriosis with symptoms like dyspareunia, dysmenorrhea, dysuria, dyschezia, and chronic pelvic pain (CPP) vary based on the organ affected, but not the illness itself. For early identification and management of bladder, ovarian, and intestine endometriosis, a higher index of concern is essential to improve the quality of life and decrease infertility. Dysmenorrhea is a fairly prevalent condition in adolescent girls, as they suffer from a variety of mental and physical symptoms that negatively impact their quality of life. Scar endometriosis has been the most common site of endometriosis in this research, with 50% of cases developing solely at the LSCS scar site. Minimal peritoneal endometriosis and also the most severe phases of the disease can be treated with laparoscopic surgery. Therefore, women with endometriosis are at a higher risk of miscarriage, and their embryo quality suffers.

The content published in Cureus is the result of clinical experience and/or research by independent individuals or organizations. Cureus is not responsible for the scientific accuracy or reliability of data or conclusions published herein. All content published within Cureus is intended only for educational, research and reference purposes. Additionally, articles published within Cureus should not be deemed a suitable substitute for the advice of a qualified health care professional. Do not disregard or avoid professional medical advice due to content published within Cureus.

The authors have declared that no competing interests exist.

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The White   House Initiative on Women's Health   Research

We have a clear goal: to fundamentally change how our nation approaches and funds women’s health research. First Lady Jill Biden, at an event announcing funding for women’s health research on february 21, 2024.

The President and First Lady launched the White House Initiative on Women’s Health Research in November of 2023 with a clear goal:  to fundamentally change how our country approaches and funds research on women’s health.

Women are over half the population, but research on women’s health has ALWAYS been underfunded and under-studied.

TOO MANY medical studies have focused on men and left women out.

TOO MANY of the medicine dosages, treatments, medical school text books, are based on men and their bodies – and that information doesn’t always apply to women.

That means there are BIG GAPS in medical research on:

• Diseases and conditions that only affect women (e.g., menopause, endometriosis)
• Diseases and conditions that disproportionately affect women (e.g., Alzheimer’s)
• Diseases and conditions that affect women and men differently (e.g., heart disease)

These gaps in research mean we know far too little about women’s health – and those gaps are bigger for women of color and women with disabilities.

We are going to change that.

Together, we will build a health care system that puts women and their lived experiences at its center. Where no woman or girl has to hear that “it’s all in your head,” or, “it’s just stress.” Where women aren’t just an after-thought, but a first-thought. Where women don’t just survive with chronic conditions, but lead long and healthy lives. First Lady of the United States on February 21, 2024. 

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Women in UK waiting almost nine years for endometriosis diagnosis, study finds

Survey of more than 4,000 people with condition reveals almost half visited their GP 10 times or more before being diagnosed

Women are waiting nearly nine years for an endometriosis diagnosis in the UK, according to research that found health professionals often minimise or dismiss symptoms.

The study by the charity Endometriosis UK suggests waiting times for a diagnosis have significantly deteriorated in the past three years, increasing to an average of eight years and 10 months, up 10 months since 2020. In Scotland, the average diagnosis time has increased by four months.

The report, based on a survey of 4,371 people who have received a diagnosis, shows that 47% of respondents had visited their GP 10 or more times with symptoms before being diagnosed, and 70% had visited five times or more.

The chief executive of Endometriosis UK, Emma Cox, said: “Taking almost nine years to get a diagnosis of endometriosis is unacceptable. Our finding that it now takes even longer to get a diagnosis of endometriosis must be a wake-up call to decision-makers to stop minimising or ignoring the significant impact endometriosis can have on both physical and mental health.”

Endometriosis is a condition where tissue similar to the womb lining grows elsewhere, such as the ovaries and fallopian tubes, and can affect fertility. Symptoms include painful periods, painful bowel movements, pain when urinating and pain during or after sex. It is thought to affect about one in 10 women of child-bearing age.

There are treatments, including hormone medication and surgery, but the lengthy delays to diagnosis have been a continuing problem that prompted the inclusion of endometriosis and gynaecological problems in the government’s women’s health strategy, launched in 2022.

The latest evidence, however, suggests waiting times have worsened. Early diagnosis is important because the disease may progress, leading to more severe physical symptoms and organ damage and restricting the ability to make informed choices that can affect fertility.

Only 10% of respondents said GPs had mentioned they suspected endometriosis at either their first or second appointment where symptoms were discussed. More than half had visited A&E at least once, and 17% of those were referred to gynaecology at their first visit. The findings were compared with a similar survey undertaken in 2019-20 before the Covid pandemic.

The report includes examples of patients’ experiences, with many being told that their pain was “normal”.

One said: “I was constantly dismissed, ignored and belittled by medical professionals telling me that my symptoms were simply due to stress and tiredness. I persevered for over 10 years desperate for help.” Another said she had been told she was “being dramatic” after going to her GP as a teenager with painful periods. Another said: “A&E nurses told me that everyone has period pain so take paracetamol and go home.”

In response to the report, the minister for the women’s health strategy, Maria Caulfield, said: “More must be done to improve women’s experiences of the healthcare system, and for those women suffering from endometriosis we have a long way to go. From getting an initial diagnosis to getting the right care and treatment, we must learn from this report.

“We launched our women’s health strategy to do just this, listen to women. Endometriosis is a priority area within our strategy, so expect to see more in this space. In addition, we are rolling our women’s health hubs across the country to support more women with specialist care required with this condition.”

An inherent challenge is that endometriosis can only currently be diagnosed by a laparoscopy. The symptoms also vary between people and overlap with other conditions, meaning it is not something a GP can definitively identify. Endometriosis UK, however, is calling on governments to commit a target of an average diagnosis time of a year or less by 2030 and urging NHS commissioners and providers to urgently reduce gynaecology waiting times.

The Royal College of Obstetricians and Gynaecologists has previously said that gynaecology waiting times increased disproportionately during the pandemic. In response to the latest report, its president, Ranee Thakar, said: “The barriers to timely diagnosis of endometriosis and other gynaecological health conditions are complex, but it is clear that more action is desperately needed.

“We need education and national communications campaigns to support women and girls to recognise their symptoms and feel confident seeking help; we need clinicians across the health service who listen to women and have the skills and expertise to diagnose and treat gynaecological conditions; and we need investment in services to ensure that we have the right equipment and training for healthcare professionals to achieve timely diagnosis.”

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Research to study new AT-04 pain relief device for endometriosis

Annapolis Valley woman concerned about wait time for endometriosis clinic

Women can wait 1-2 years for a referral and another 12-18 months to be treated.

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Victoria Martin has undergone four operations because of her endometriosis, but those procedures have not ended the pain and fatigue, nor the emotional strain she is forced to endure as a result of the disease.

The 36-year-old Wolfville woman, who is pregnant with her second child, is hoping the IWK's Endometriosis and Chronic Pelvic Pain Clinic will find a way to relieve her symptoms so she can function normally and some day return to the workplace.

"I'm concerned because, sadly, I'm used to [dealing] with the pain and the flare [ups], but I'm concerned because last time that happened, and I was able to receive care somewhere else, the damage was pretty extensive," said Martin, referring to her 2021 operation in France, where she was born and grew up. "So I'm just wondering where we're at three years later."

Endometriosis is a condition in which tissue similar to that normally found inside the uterus, grows outside of it instead. It's often very painful and the buildup of abnormal tissue around organs in the abdomen can cause problems with pregnancy, menstruation and overall health.

Despite her struggle, Martin considers herself fortunate to live only an hour away from Halifax, where specialized care has been available for three years .

But after six months on the waitlist, in the midst of a higher-risk pregnancy, she would like to be seen, at the very least, to get an MRI to determine how the disease has progressed.

"Although I'm not sure will be offered to me, in my personal case, I've had feedback from a couple of close friends who have been through the clinic and, although a very long wait — a year to get the surgeries — [they] were really, really happy with the care that they got," she said.

According to the clinic's medical co-director, Dr. Elizabeth Randle, patients are currently waiting a year to 18 months to be seen, depending on the urgency of their medical situation.

That doesn't include the year to two-year-long wait simply to be referred to the clinic. Each referral is individually triaged by a physician and more urgent cases are seen sooner. 

"The big delays, at this point, are the lack of primary care providers, a lack of publicly funded resources to allow us to provide the best evidence-based care to this patient population," said Randle. "[Endometriosis] is so challenging to treat that we need more funding from a manpower standpoint, as well as from a research standpoint to really continue to move the needle on treating this disease."

Clinic had 247 patient visits last year

The clinic is made up of two gynaecologists, one anesthesiologist, a nurse practitioner, a social worker, a physiotherapist and a dietitian. Because they have other duties, including research, the clinic sees patients one day a week.

According to the IWK, the clinic handled 247 patient visits in 2023 — excluding physiotherapy and social work. Most of those patients were Nova Scotians seeking care, although there are patients from New Brunswick and P.E.I.

Even with the backlog, Randle says the lack of understanding about endometriosis means many more people are suffering without knowing they have the disease.

"There's likely many more patients out there that we don't even know about right now, who are suffering in silence and have felt let down by the medical system over the decades that they've been trying to seek care," said Randle. "We hear that story time and again from patients who are able to access our care."

That was Faith Lamoureux's experience. The 28-year-old Dartmouth woman had a hysterectomy last April because of the extensive damage caused by disease before it was properly diagnosed. Doctors chose to operate because they thought the pain might be linked to a cancerous growth.

Lamoureux said she was a frequent visitor to ERs throughout her 20s.

"I would be in so much pain that I couldn't get out of my bed so my husband would have to carry me to the car, carry me to the emergency room," said the small business owner. "Some days I'd wake up and I'd feel like something was imploding inside me, and some days I'd wake up and I just couldn't leave [the house]."

'We need more funding'

She said she was often prescribed anti-inflammatory medication, but that eventually caused stomach problems that were sometimes even more painful than the endometriosis.

"It kind-of barrel-rolled into more issues."

An emergency room physician suggested Lamoureux might have endometriosis but he told her he didn't know much about it, and neither did family and friends she talked to about her health problems.

She was at Province House on March 1, to mark the province's first ever Endometriosis Awareness Month to talk publicly about her experience in the hopes increased awareness will lead to more resources for women who suffer from the disease.

Randle would love to have more resources.

"We need more funding for people to fill the gaps in care, we need more funding to facilitate people getting referrals on a more expedient basis, we need more money for the allied health providers, we need more money to fund the research, we need money from a pharmacare standpoint," said Randle. "So we need money."

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ABOUT THE AUTHOR

Jean Laroche has been a CBC reporter since 1987. He's been covering Nova Scotia politics since 1995 and has been at Province House longer than any sitting member.